Cysteine, N-acetylcysteine, and penicillamine related compounds, pharmaceutical compositions thereof, and methods of use

ABSTRACT

Cysteine, N-acetylcysteine, and penicillamine related compounds, pharmaceutical compositions comprising the cysteine, N-acetylcysteine, and penicillamine related compounds, and methods of using cysteine, N-acetylcysteine, and penicillamine related compounds and pharmaceutical compositions thereof for treating liver, kidney, lung, neurological, inflammatory, and autoimmune disorders including paracetamol overdose, non-alcoholic steatohepatitis, Wilson&#39;s disease, cystinuria, irritable bowel disorder, ulcerative colitis, rheumatoid arthritis, chronic obstructive pulmonary disease, interstitial lung disease, asthma, cystic fibrosis, Parkinson&#39;s disease, and Huntington&#39;s disease.

FIELD

Disclosed herein are cysteine, N-acetylcysteine, and penicillamineprodrugs, pharmaceutical compositions comprising cysteine,N-acetylcysteine, and penicillamine prodrugs, and methods of usingcysteine, N-acetylcysteine, and penicillamine prodrugs andpharmaceutical compositions thereof for treating liver, kidney, lung,neurological, inflammatory, and autoimmune disorders includingparacetamol overdose, non-alcoholic steatohepatitis, Wilson's disease,cystinuria, irritable bowel disorder, ulcerative colitis, rheumatoidarthritis, chronic obstructive pulmonary disease, interstitial lungdisease, asthma, cystic fibrosis, Parkinson's disease, and Huntington'sdisease.

BACKGROUND

N-Acetyl-L-cysteine (NAC) is approved in United States a mucolytic agentfor the treatment of chronic bronchopulmonary disease (chronicemphysema, emphysema with bronchitis, chronic asthmatic bronchitis,tuberculosis, bronchiectasis and primary amyloidosis of the lung) and asan antidote to prevent or lessen hepatic injury following anacetaminophen overdose. D-Penicillamine is also approved in UnitedStates for the treatment of Wilson's disease and cystinuria. Both drugshave been proposed for use in treating a wide range of immunological,autoimmune, inflammatory, and/or neurological diseases and conditions.

NAC has been proposed for use in treating interstitial lung disease(Grandjean et al., Clin Ther 2000, 22 (2), 209-21; and Stey et al., Eur.Respir. J. 2000, 16 (2), 253-62); kidney disease induced byradio-contrasting agent (Tepel et al., N. Engl. J. Med. 2000, 343 (3),180-4); liver disease such as non-alcoholic steatohepatitis (Khoshbatenet al., Hepatitis Montly 2010, 10 (1), 12-16); and psychiatric disorderssuch as schizophrenia, bipolar disorder, trichotillomania, skin picking,autism, and obsessive-compulsive disorder (Dean et al., Journal ofPsychiatry & Neuroscience: JPN 1982, 36 (2), 78-86; Berk et al., TrendsPharmacol. Sci. 2013, 34 (3), 167-77; and Bavarsad et al., Brain andBehavior 2014, 4 (2), 108-22).

D-Penicillamine has been proposed for use in treating scleroderma (Steenet al., Annals of internal medicine 1982, 97 (5), 652-659) andrheumatoid arthritis (Camp, et al., Proceedings of the Royal Society ofMedicine 1977, 70 (2), 67-69).

The mechanisms of action of NAC and D-penicillamine for the approved andproposed treatments probably involve a number of pathways.N-acetyl-L-cysteine acts as a prodrug to L-cysteine, which acts as aprecursor to the important biological antioxidant glutathione.D-penicillamine possesses a reactive thiol group, which can bind to andhelp eliminate heavy metal ions such copper and lead from the body.

However, both NAC and D-penicillamine exhibit poor oral absorptioncharacteristics. NAC has an oral bioavailability of only 4-10% (Olssonet al., Eur J Clin Pharmacol. 1988, 34 (1), 77-82) while D-penicillamineshowed a high degree of interpatient oral variability (Merck & Co.,Inc.). Both compounds can undergo oxidation in the intestine to formdisulfides.

SUMMARY

NAC and D-penicillamine prodrugs having better biochemical stability(i.e., less disulfide or mixed disulfides formation), highgastrointestinal permeability and/or absorption, improved solubility,ordered hydrolysis (i.e., preferential cleavage of promoieties), andminimal degradation/cleavage in the gut lumen or enterocyte cytoplasmare desirable. Such NAC and D-penicillamine prodrugs, which providehigher oral bioavailability and plasma levels of the parent compounds,NAC and D-penicillamine, may: enhance the efficacy/responder ratecompared to present NAC and D-penicillamine; facilitate the use of lowerdoses, reduce dosing frequency, and standardize dosing regimens; reducefood effects; reduce gastrointestinal side effects/toxicity; and reduceinterpatient treatment variability.

In a first aspect, compounds of Formula (I) are provided:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   each R¹ is chosen from hydrogen and methyl; R² is chosen from        hydrogen, C₁₋₆ alkyl, C₁₋₆ heteroalkyl, C₃₋₁₂ cycloalkyl, C₃₋₁₂        heterocycloalkyl, C₅₋₁₀ aryl, and C₅₋₁₀ heteroaryl;    -   W¹ is chosen from a compound of Formula (I-a) and Formula (I-b);        and    -   W² is chosen from hydrogen and a compound of Formula (I-a),        Formula (I-b), and Formula (I-c):

wherein

-   -   R³, R⁴, R⁵, R⁶, and R⁷ are independently chosen from hydrogen,        C₁₋₆ alkyl, C₁₋₆ heteroalkyl, C₃₋₁₂ cycloalkyl, C₃₋₁₂        heterocycloalkyl, C₅₋₁₀ aryl, and C₅₋₁₀ heteroaryl; and    -   Y¹ is chosen from a bond and —O—.

In a second aspect, pharmaceutical compositions are provided comprisinga compound of Formula (I) and at least one pharmaceutically acceptablevehicle.

In a third aspect, methods of treating a disease in a patient areprovided comprising administering to a patient in need of such treatmenta pharmaceutical composition comprising a therapeutically effectiveamount of a compound of Formula (I). In certain embodiments, the diseaseis chosen from a liver disease, a lung disease, a neurodegenerativedisease, an inflammatory disease, and an autoimmune disease including,for example, cirrhosis, hepatitis, cystinuria, scleroderma, multiplesclerosis, psoriasis, irritable bowel disorder, ulcerative colitis,arthritis, chronic obstructive pulmonary disease, asthma, Parkinson'sdisease, Huntington's disease, and amyotrophic lateral sclerosis.

DETAILED DESCRIPTION Definitions

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a moiety or substituent. For example,—CONH₂ is bonded through the carbon atom.

“Alkyl” refers to a saturated or unsaturated, branched, orstraight-chain, monovalent hydrocarbon radical derived by the removal ofone hydrogen atom from a single carbon atom of a parent alkane, alkene,or alkyne. Examples of alkyl groups include, but are not limited to,methyl; ethyls such as ethanyl, ethenyl, and ethynyl; propyls such aspropan-1-yl, propan-2-yl, prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl(allyl), prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls suchas butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl,but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, but-1-yn-1-yl,but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

The term “alkyl” is specifically intended to include groups having anydegree or level of saturation, i.e., groups having exclusively singlecarbon-carbon bonds, groups having one or more double carbon-carbonbonds, groups having one or more triple carbon-carbon bonds, and groupshaving combinations of single, double, and triple carbon-carbon bonds.Where a specific level of saturation is intended, the terms alkanyl,alkenyl, and alkynyl are used. In certain embodiments, an alkyl groupcan have from 1 to 20 carbon atoms (C₁₋₂₀) in certain embodiments, from1 to 10 carbon atoms (C₁₋₁₀, in certain embodiments from 1 to 8 carbonatoms (C₁₋₈), in certain embodiments, from 1 to 6 carbon atoms (C₁₋₆),in certain embodiments from 1 to 4 carbon atoms (C₁₋₄), and in certainembodiments, from 1 to 3 carbon atoms (C₁₋₃).

“Amino acid side chain” includes the side chains of naturally occurringstandard amino acids, side chains of naturally occurring non-standardamino acids, and side chains of non-naturally occurring amino acidderivatives. In certain embodiments the amino acid side chain isselected from a hydrogen, methyl, isopropyl, sec-butyl, phenyl, benzyl,p-hydroxybenzyl, 1H-imidazol-5-ylmethyl, 1H-indol-3-ylmethyl, —CH₂OH,—CH₂CH₂OH, —CH(OH)CH₃, —CH₂CH₂SCH₃, —CH₂CONH₂, —CH₂COOH, —CH₂CH₂CONH₂,—CH₂CH₂COOH, —(CH₂)₃NHC(═NH)NH₂, —(CH₂)₃NH₂, —(CH₂)₃NHCOCH₃,—(CH₂)₃NHCHO, —(CH₂)₄NHC(═NH)NH₂, —(CH₂)₄NH₂, —(CH₂)₄NHCOCH₃,—(CH₂)₄NHCHO, —(CH₂)₃NHCONH₂, —(CH₂)₄NHCONH₂, and —CH₂CH₂CH(OH)CH₂NH₂.

In certain embodiments the amino acid side chain is bonded to a chiralcarbon atom that is in the (R) configuration, and in certainembodiments, the (S) configuration.

“Aryl” refers to a monovalent aromatic hydrocarbon radical derived bythe removal of one hydrogen atom from a single carbon atom of a parentaromatic ring system. Aryl benzene; bicyclic ring systems wherein atleast one ring is carbocyclic and aromatic, for example, naphthalene,indane, and tetralin; and tricyclic ring systems wherein at least onering is carbocyclic and aromatic, for example, fluorene. Arylencompasses multiple ring systems having at least one carbocyclicaromatic ring fused to at least one carbocyclic aromatic ring,cycloalkyl ring, or heterocycloalkyl ring. For example, aryl includes aphenyl ring fused to a 5- to 7-membered heterocycloalkyl ring containingone or more heteroatoms chosen from N, O, and S. For such fused,bicyclic ring systems wherein only one of the rings is a carbocyclicaromatic ring, the radical carbon atom may be at the carbocyclicaromatic ring or at the heterocycloalkyl ring. Examples of aryl groupsinclude, but are not limited to, groups derived from aceanthrylene,acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene,hexylene, as-indacene, s-indacene, indane, indene, naphthalene,octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene,pentalene, pentaphene, perylene, phenalene, phenanthrene, picene,pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene,and the like. In certain embodiments, an aryl group can have from 6 to20 carbon atoms (C₆₋₂₀), from 6 to 12 carbon atoms (C₆₋₁₂), from 6 to 10carbon atoms (C₆₋₁₀), and in certain embodiments from 6 to 8 carbonatoms (C₆₋₈). Aryl, however, does not encompass or overlap in any waywith heteroaryl, separately defined herein.

“Compounds” of Formula (I) disclosed herein include any specificcompounds within the formula. Compounds may be identified either bytheir chemical structure and/or chemical name. Compounds are named usingAccelrys Draw 4.1 SP1, version MDL.Draw.Editor 4.1. 100.70 (Accelrys,Inc., San Diego, Calif.). When the chemical structure and chemical nameconflict, the chemical structure is determinative of the identity of thecompound. The compounds described herein may comprise one or more chiralcenters and/or double bonds and therefore may exist as stereoisomerssuch as double-bond isomers (i.e., geometric isomers), enantiomers, ordiastereomers. Accordingly, any chemical structures within the scope ofthe specification depicted, in whole or in part, with a relativeconfiguration encompass all possible enantiomers and stereoisomers ofthe illustrated compounds including the stereoisomerically pure form(e.g., geometrically pure, enantiomerically pure, or diastereomericallypure) and enantiomeric and stereoisomeric mixtures. Enantiomeric andstereoisomeric mixtures may be resolved into their component enantiomersor stereoisomers using separation techniques or chiral synthesistechniques well known to the skilled artisan. Compounds of Formula (I)include, but are not limited to, optical isomers of compounds of Formula(I), racemates thereof, and other mixtures thereof. In such embodiments,a single enantiomer or diastereomer, i.e., optically active form can beobtained by asymmetric synthesis or by resolution of the racemates.Resolution of the racemates may be accomplished, for example, byconventional methods such as crystallization in the presence of aresolving agent, or chromatography using, for example, chiral stationaryphases. Not withstanding the foregoing, in compounds of Formula (I) theconfiguration of the illustrated double bond is only in the Econfiguration (i.e. trans configuration).

Compounds of Formula (I) may also exist in several tautomeric formsincluding the enol form, the keto form, and mixtures thereof.Accordingly, the chemical structures depicted herein encompass allpossible tautomeric forms of the illustrated compounds. Compounds ofFormula (I) also include isotopically labeled compounds where one ormore atoms have an atomic mass different from the atomic massconventionally found in nature. Examples of isotopes that may beincorporated into the compounds disclosed herein include, but are notlimited to, ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, etc. Compounds mayexist in unsolvated forms as well as solvated forms, including hydratedforms and as N-oxides. In general, compounds as referred to herein maybe free acid, hydrated, solvated, or N-oxides. Certain compounds mayexist in multiple crystalline, co-crystalline, or amorphous forms.Compounds of Formula (I) include pharmaceutically acceptable saltsthereof, or pharmaceutically acceptable solvates of the free acid formof any of the foregoing, as well as crystalline forms of any of theforegoing.

Compounds of Formula (I) also include solvates. A solvate refers to amolecular complex of a compound with one or more solvent molecules in astoichiometric or non-stoichiometric amount. Such solvent molecules arethose commonly used in the pharmaceutical art, which are known to beinnocuous to a patient, e.g., water, ethanol, and the like. A molecularcomplex of a compound or moiety of a compound and a solvent can bestabilized by non-covalent intra-molecular forces such as, for example,electrostatic forces, van der Waals forces, or hydrogen bonds. The term“hydrate” refers to a solvate in which the one or more solvent moleculesis water.

Further, when partial structures of the compounds are illustrated, anasterisk (*) or a wavy line (

) indicates the point of attachment of the partial structure to the restof the molecule.

“Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkylradical. Where a specific level of saturation is intended, thenomenclature cycloalkanyl or cycloalkenyl is used. Examples ofcycloalkyl groups include, but are not limited to, groups derived fromcyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like. Incertain embodiments, a cycloalkyl group is C₃₋₁₅ cycloalkyl, C₃₋₁₂cycloalkyl, and in certain embodiments, C₃₋₈ cycloalkyl.

“Disease” refers to a disease, disorder, condition, or symptom of any ofthe foregoing.

“Drug” as defined under 21 U.S.C. §321(g)(1) means “(A) articlesrecognized in the official United States Pharmacopoeia, officialHomeopathic Pharmacopoeia of the United States, or official NationalFormulary, or any supplement to any of them; and (B) articles intendedfor use in the diagnosis, cure, mitigation, treatment, or prevention ofdisease in man or other animals; and (C) articles (other than food)intended to affect the structure or any function of the body of man orother animals . . . .”

“Halogen” refers to a fluoro, chloro, bromo, or iodo group. In certainembodiments, halogen refers to a chloro group.

“Heteroalkyl” by itself or as part of another substituent refers to analkyl group in which one or more of the carbon atoms (and certainassociated hydrogen atoms) are independently replaced with the same ordifferent heteroatomic groups. Examples of heteroatomic groups include,but are not limited to, —O—, —S—, —O—O—, —S—S—, —O—S—, —NR⁹¹, ═N—N═,—N═N—, —N═N—NR⁹¹—, —PR⁹¹—, —P(O)₂—, —POR⁹¹—, —O—P(O)₂—, —SO—, —SO₂—,—Sn(R⁹¹)₂—, and the like, where each R⁹¹ is independently chosen fromhydrogen, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₆₋₁₂ aryl, substitutedC₆₋₁₂ aryl, C₇₋₁₈ arylalkyl, substituted C₇₋₁₈ arylalkyl, C₃₋₇cycloalkyl, substituted C₃₋₇ cycloalkyl, C₃₋₇ heterocycloalkyl,substituted C₃₋₇ heterocycloalkyl, C₁₋₆ heteroalkyl, substituted C₁₋₆heteroalkyl, C₆₋₁₂ heteroaryl, substituted C₆₋₁₂ heteroaryl, C₇₋₁₈heteroarylalkyl, or substituted C₇₋₁₈ heteroarylalkyl. Reference to, forexample, a C₁₋₆ heteroalkyl, means a C₁₋₆ alkyl group in which at leastone of the carbon atoms (and certain associated hydrogen atoms) isreplaced with a heteroatom. For example C₁₋₆ heteroalkyl includes groupshaving five carbon atoms and one heteroatom, groups having four carbonatoms and two heteroatoms, etc. In certain embodiments, each R⁹¹ isindependently chosen from hydrogen and C₁₋₃ alkyl. In certainembodiments, a heteroatomic group is chosen from —O—, —S—, —NH—,—N(CH₃)—, and —SO₂—; and in certain embodiments, the heteroatomic groupis —O—.

“Heteroaryl” by itself or as part of another substituent refers to aaryl group in which one or more of the carbon atoms (and certainassociated hydrogen atoms) are independently replaced with the same ordifferent heteroatomic groups. Examples of heteroatomic groups include,but are not limited to, —O—, —S—, —O—O—, —S—S—, —O—S—, —NR⁹¹, ═N—N═,—N═N—, —N═N—NR⁹¹—, —PR⁹¹—, —P(O)₂—, —POR⁹¹—, —O—P(O)₂—, —SO—, —SO₂—,—Sn(R⁹¹)₂—, and the like, where each R⁹¹ is independently chosen fromhydrogen, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₆₋₁₂ aryl, substitutedC₆₋₁₂ aryl, C₇₋₁₈ arylalkyl, substituted C₇₋₁₈ arylalkyl, C₃₋₇cycloalkyl, substituted C₃₋₇ cycloalkyl, C₃₋₇ heterocycloalkyl,substituted C₃₋₇ heterocycloalkyl, C₁₋₆ heteroalkyl, substituted C₁₋₆heteroalkyl, C₆₋₁₂ heteroaryl, substituted C₆₋₁₂ heteroaryl, C₇₋₁₈heteroarylalkyl, or substituted C₇₋₁₈ heteroarylalkyl.

Heteroaryl encompasses multiple ring systems having at least oneheteroaromatic ring fused to at least one other ring, which can bearomatic or non-aromatic. For example, heteroaryl encompasses bicyclicrings in which one ring is heteroaromatic and the second ring is aheterocycloalkyl ring. For such fused, bicyclic heteroaryl ring systemswherein only one of the rings contains one or more heteroatoms, theradical carbon may be at the aromatic ring or at the heterocycloalkylring.

Examples of heteroaryl groups include, but are not limited to, groupsderived from acridine, arsindole, carbazole, β-carboline, chromane,chromene, cinnoline, furan, imidazole, indazole, indole, indoline,indolizine, isobenzofuran, isochromene, isoindole, isoindoline,isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole,oxazole, perimidine, phenanthridine, phenanthroline, phenazine,phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine,pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline,quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene,triazole, xanthene, thiazolidine, oxazolidine, and the like. In certainembodiments, a heteroaryl group is from 4- to 20-membered heteroaryl(C₄₋₂₀), and in certain embodiments from 4- to 12-membered heteroaryl(C₄₋₁₀). In certain embodiments, heteroaryl groups are those derivedfrom thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine,quinoline, imidazole, oxazole, or pyrazine. For example, in certainembodiments, C₅ heteroaryl can be furyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, isothiazolyl, and isoxazolyl.

“Heterocycloalkyl” by itself or as part of another substituent refers toa cycloalkyl group in which one or more of the carbon atoms (and certainassociated hydrogen atoms) are independently replaced with the same ordifferent heteroatomic groups. Examples of heteroatomic groups include,but are not limited to, —O—, —S—, —O—O—, —S—S—, —O—S—, —NR⁹¹, ═N—N═,—N═N—, —N═N—NR⁹¹—, —PR⁹¹—, —P(O)₂—, —POR⁹¹—, —O—P(O)₂—, —SO—, —SO₂—,—Sn(R⁹¹)₂—, and the like, where each R⁹¹ is independently chosen fromhydrogen, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₆₋₁₂ aryl, substitutedC₆₋₁₂ aryl, C₇₋₁₈ arylalkyl, substituted C₇₋₁₈ arylalkyl, C₃₋₇cycloalkyl, substituted C₃₋₇ cycloalkyl, C₃₋₇ heterocycloalkyl,substituted C₃₋₇ heterocycloalkyl, C₁₋₆ heteroalkyl, substituted C₁₋₆heteroalkyl, C₆₋₁₂ heteroaryl, substituted C₆₋₁₂ heteroaryl, C₇₋₁₈heteroarylalkyl, or substituted C₇₋₁₈ heteroarylalkyl. Reference to, forexample, a C₃₋₆ heterocycloalkyl, means a C₃₋₆ cycloalkyl group in whichat least one of the carbon atoms (and certain associated hydrogen atoms)is replaced with a heteroatom. For example C₃₋₆ heterocycloalkylincludes groups having five carbon atoms and one heteroatom, groupshaving four carbon atoms and two heteroatoms, etc. In certainembodiments, each R⁹¹ is independently chosen from hydrogen and C₁₋₃alkyl. In certain embodiments, a heteroatomic group is chosen from —O—,—S—, —NH—, —N(CH₃)—, and —SO₂—; and in certain embodiments, theheteroatomic group is —O—.

“Parent aromatic ring system” refers to an unsaturated cyclic orpolycyclic ring system having a conjugated π (pi) electron system.Included within the definition of “parent aromatic ring system” arefused ring systems in which one or more of the rings are aromatic andone or more of the rings are saturated or unsaturated, such as, forexample, fluorene, indane, indene, phenalene, etc. Examples of parentaromatic ring systems include, but are not limited to, aceanthrylene,acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene,hexylene, as-indacene, s-indacene, indane, indene, naphthalene,octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene,pentalene, pentaphene, perylene, phenalene, phenanthrene, picene,pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene,and the like.

“Parent heteroaromatic ring system” refers to an aromatic ring system inwhich one or more carbon atoms (and any associated hydrogen atoms) areindependently replaced with the same or different heteroatom in such away as to maintain the continuous π-electron system characteristic ofaromatic systems and a number of out-of-plane π-electrons correspondingto the Hückel rule (4n+2). Examples of heteroatoms to replace the carbonatoms include, but are not limited to, N, P, O, S, and Si, etc.Specifically included within the definition of “parent hetero aromaticring systems” are fused ring systems in which one or more of the ringsare aromatic and one or more of the rings are saturated or unsaturated,such as, for example, arsindole, benzodioxan, benzofuran, chromane,chromene, indole, indoline, xanthene, etc. Examples of parentheteroaromatic ring systems include, but are not limited to, arsindole,carbazole, β-carboline, chromane, chromene, cinnoline, furan, imidazole,indazole, indole, indoline, indolizine, isobenzofuran, isochromene,isoindole, isoindoline, isoquinoline, isothiazole, isoxazole,naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine,phenanthroline, phenazine, phthalazine, pteridine, purine, pyran,pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole,pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene,thiazolidine, oxazolidine, and the like.

“Patient” refers to a mammal, for example, a human.

“Pharmaceutically acceptable” refers to approved or approvable by aregulatory agency of the Federal or a state government or listed in theU.S. Pharmacopoeia or other generally recognized pharmacopoeia for usein animals, and more particularly in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound, whichpossesses the desired pharmacological activity of the parent compound.Such salts include acid addition salts, formed with inorganic acids suchas hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; andsalts formed when an acidic proton present in the parent compound isreplaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine, andthe like. In certain embodiments, a pharmaceutically acceptable salt isthe hydrochloride salt. In certain embodiments, a pharmaceuticallyacceptable salt is the sodium salt.

“Pharmaceutically acceptable vehicle” refers to a pharmaceuticallyacceptable diluent, a pharmaceutically acceptable adjuvant, apharmaceutically acceptable excipient, a pharmaceutically acceptablecarrier, or a combination of any of the foregoing with which a compoundprovided by the present disclosure may be administered to a patient andwhich does not destroy the pharmacological activity thereof and which isnon-toxic when administered in doses sufficient to provide atherapeutically effective amount of the compound.

“Pharmaceutical composition” refers to a compound of Formula (I) and atleast one pharmaceutically acceptable vehicle, with which the compoundof Formula (I) is administered to a patient.

“Substituted” refers to a group in which one or more hydrogen atoms areindependently replaced with the same or substituent group(s). In certainembodiments, each substituent group is independently chosen fromhalogen, —OH, —CN, —CF₃, ═O, —NO₂, benzyl, —C(O)NR²¹ ₂, —R²¹, —OR²¹,—COOR²¹, —C(R²¹)NH₂, —C(O)C(R²¹)NH₂, —C(R²¹)C(O)OH, —NC(R²¹)C(O)OH,—NR²¹ ₂, —NR²¹C(O)R²¹, and —O(O)R²¹, wherein each R²¹ is independentlychosen from hydrogen, C₁₋₆ alkyl, C₁₋₆ heteroalkyl, C₃₋₁₂ cycloalkyl,C₅₋₁₀ aryl, C₅₋₁₀ heteroaryl, and amino acid side chain. In certainembodiments, each substituent group is independently chosen fromhalogen, —OH, —CN, —CF₃, —NO₂, benzyl, —R²¹, —OR²¹, —C(O)R²¹, —COOR²¹,—C(R²¹)NH₂, —C(O)C(R²¹)NH₂, —C(R²¹)C(O)OH, —NC(R²¹)C(O)OH, —NR²¹ ₂,—NR²¹C(O)R²¹, and —O(O)R²¹, wherein each R²¹ is independently chosenfrom hydrogen, C₁₋₆ alkyl, C₁₋₆ heteroalkyl, C₃₋₁₂ cycloalkyl, C₅₋₁₀aryl, C₅₋₁₀ heteroaryl, and amino acid side chain. In certainembodiments, each substituent group is independently chosen fromhalogen, —OH, —CN, —CF₃, ═O, —NO₂, benzyl, —C(O)NR²¹ ₂, —R²¹, —OR²¹,—C(O)R²¹, —COOR²¹, —NR²¹ ₂, —NR²¹C(O)R²¹, and —O(O)R²¹, wherein each R²¹is independently chosen from hydrogen, C₁₋₆ alkyl, C₁₋₆ heteroalkyl,C₃₋₁₂ cycloalkyl, C₅₋₁₀ aryl, C₅₋₁₀ heteroaryl, and amino acid sidechain. In certain embodiments, each substituent group is independentlychosen from —OH, —NH₂, C₁₋₄ alkyl, and amino acid side chain. In certainembodiments, each substituent group is independently chosen from —OH,—C(O)NR²¹ ₂, —R²¹, —C(O)R²¹, —COOR²¹, —C(R²¹)NH₂, —C(O)C(R²¹)NH₂,—C(R²¹)C(O)OH, and —NC(R²¹)C(O)OH, wherein each R²¹ is independentlychosen from a hydrogen, methyl, isopropyl, sec-butyl, phenyl, benzyl,p-hydroxybenzyl, 1H-imidazol-5-ylmethyl, 1H-indol-3-ylmethyl, —CH₂OH,—CH(OH)CH₃, —CH₂CH₂SCH₃, —CH₂CONH₂, —CH₂COOH, —CH₂CH₂CONH₂, —CH₂CH₂COOH,—(CH₂)₃NHC(═NH)NH₂, —(CH₂)₃NH₂, —(CH₂)₃NHCOCH₃, —(CH₂)₃NHCHO,—(CH₂)₄NHC(═NH)NH₂, —(CH₂)₄NH₂, —(CH₂)₄NHCOCH₃, —(CH₂)₄NHCHO,—(CH₂)₃NHCONH₂, —(CH₂)₄NHCONH₂, and —CH₂CH₂CH(OH)CH₂NH₂.

“Treating” or “treatment” of any disease refers to reversing,alleviating, arresting, or ameliorating a disease or at least one of theclinical symptoms of a disease, reducing the risk of acquiring a diseaseor at least one of the clinical symptoms of a disease, inhibiting theprogress of a disease or at least one of the clinical symptoms of thedisease or reducing the risk of developing a disease or at least one ofthe clinical symptoms of a disease. “Treating” or “treatment” alsorefers to inhibiting the disease, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both, and to inhibiting atleast one physical parameter that may or may not be discernible to thepatient. In certain embodiments, “treating” or “treatment” refers todelaying the onset of the disease or at least one or more symptomsthereof in a patient which may be exposed to or predisposed to a diseaseeven though that patient does not yet experience or display symptoms ofthe disease.

“Therapeutically effective amount” refers to the amount of a compoundthat, when administered to a subject for treating a disease, or at leastone of the clinical symptoms of a disease, is sufficient to affect suchtreatment of the disease or symptom thereof. The “therapeuticallyeffective amount” may vary depending, for example, on the compound, thedisease and/or symptoms of the disease, severity of the disease and/orsymptoms of the disease or disorder, the age, weight, and/or health ofthe patient to be treated, and the judgment of the prescribingphysician. An appropriate amount in any given instance may beascertained by those skilled in the art or capable of determination byroutine experimentation.

“Therapeutically effective dose” refers to a dose that provideseffective treatment of a disease or disorder in a patient. Atherapeutically effective dose may vary from compound to compound, andfrom patient to patient, and may depend upon factors such as thecondition of the patient and the route of delivery. A therapeuticallyeffective dose may be determined in accordance with routinepharmacological procedures known to those skilled in the art.

Reference is now made in detail to certain embodiments of compounds,compositions, and methods. The disclosed embodiments are not intended tobe limiting of the claims. To the contrary, the claims are intended tocover all alternatives, modifications, and equivalents.

Compounds

Certain embodiments provide a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   each R¹ is chosen from hydrogen and methyl;    -   R² is chosen from hydrogen, C₁₋₆ alkyl, C₁₋₆ heteroalkyl, C₃₋₁₂        cycloalkyl, C₃₋₁₂ heterocycloalkyl, C₅₋₁₀ aryl, and C₅₋₁₀        heteroaryl;    -   W¹ is chosen from a compound of Formula (I-a) and Formula (I-b);        and    -   W² is chosen from hydrogen and a compound of Formula (I-a),        Formula (I-b), and Formula (I-c):

wherein

-   -   R³, R⁴, R⁵, R⁶, and R⁷ are independently chosen from hydrogen,        C₁₋₆ alkyl, C₁₋₆ heteroalkyl, C₃₋₁₂ cycloalkyl, C₃₋₁₂        heterocycloalkyl, C₅₋₁₀ aryl, and C₅₋₁₀ heteroaryl; and    -   Y¹ is chosen from a bond and —O—.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen.

In certain embodiments of a compound of Formula (I), each R¹ is methyl.

In certain embodiments of a compound of Formula (I), R², R³, R⁴, R⁵, R⁶,and R⁷ are independently chosen from hydrogen, C₁₋₆ alkyl, C₁₋₆heteroalkyl, C₃₋₁₂ cycloalkyl, C₃₋₁₂ heterocycloalkyl, C₅₋₁₀ aryl, andC₅₋₁₀ heteroaryl.

In certain embodiments of a compound of Formula (I), R², R³, R⁴, R⁵, R⁶,and R⁷ are independently chosen from hydrogen and C₁₋₆ alkyl.

In certain embodiments of a compound of Formula (I), R², R³, R⁴, R⁵, R⁶,and R⁷ are independently chosen from hydrogen, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, pentyl-2-yl,2-methylbutyl, isopentyl, 3-methylbutan-2-yl, neopentyl, tert-pentyl,n-hexyl, hexan-2-yl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,3-methylpentan-2-yl, 4-methylpentan-2-yl, 2,3-dimethylbutyl, and3,3-dimethylbutyl.

In certain embodiments of a compound of Formula (I), R², R³, R⁴, R⁵, R⁶,and R⁷ are independently chosen from hydrogen and C₁₋₆ heteroalkyl.

In certain embodiments of a compound of Formula (I), R², R³, R⁴, R⁵, R⁶,and R⁷ are independently chosen from hydrogen, methoxymethyl,2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl, 3-ethoxypropyl, and4-methoxybutyl.

In certain embodiments of a compound of Formula (I), R², R³, R⁴, R⁵, R⁶,and R⁷ are independently chosen from hydrogen and C₃₋₁₂ cycloalkyl.

In certain embodiments of a compound of Formula (I), R², R³, R⁴, R⁵, R⁶,and R⁷ are independently chosen from hydrogen, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

In certain embodiments of a compound of Formula (I), R², R³, R⁴, R⁵, R⁶,and R⁷ are independently chosen from hydrogen and C₃₋₁₂heterocycloalkyl.

In certain embodiments of a compound of Formula (I), R², R³, R⁴, R⁵, R⁶,and R⁷ are independently chosen from hydrogen; azepan-1-yl;azetidin-1-yl; 2H-azet-1-yl; aziridin-1-yl; azirin-1-yl; azocan-1-yl;1,2-dihydroimidazol-3-yl; 2,4-dihydroimidazol-3-yl;4,5-dihydroimidazol-1-yl; 1,3-dihydropyrazol-2-yl;1,5-dihydropyrazol-2-yl; 3,4-dihydropyrazol-2-yl;2,3-dihydropyrrol-1-yl; 2,5-dihydropyrrol-1-yl;1,5-dihydro-1,2,4-triazol-4-yl; 3,5-dihydro-1,2,4-triazol-4-yl;4,5-dihydrotriazol-1-yl; 1,3,5-dioxazinan-5-yl; 1,3,2-dioxazol-2-yl;hexahydropyrimidin-1-yl; imidazolidin-1-yl; morpholin-4-yl;1,3-oxazetidin-3-yl; oxazetidin-2-yl; 1,3-oxazinan-3-yl;oxazolidin-3-yl; 2H-oxazol-3-yl; piperazin-1-yl; 1-piperidyl;pyrazolidin-1-yl; and pyrrolidin-1-yl.

In certain embodiments of a compound of Formula (I), R², R³, R⁴, R⁵, R⁶,and R⁷ are independently chosen from hydrogen, morpholin-4-yl;oxazolidin-3-yl; 1-piperidyl; pyrrolidin-1-yl; 2,5-dioxopyrrolidin-1-yl;and 2-oxopyrrolidin-1-yl.

In certain embodiments of a compound of Formula (I), R², R³, R⁴, R⁵, R⁶,and R⁷ are independently chosen from hydrogen and morpholin-4-yl.

In certain embodiments of a compound of Formula (I), R², R³, R⁴, R⁵, R⁶,and R⁷ are independently chosen from hydrogen and C₅₋₁₀ aryl.

In certain embodiments of a compound of Formula (I), R², R³, R⁴, R⁵, R⁶,and R⁷ are independently chosen from hydrogen, phenyl, phenylphenyl, andnaphthyl.

In certain embodiments of a compound of Formula (I), R², R³, R⁴, R⁵, R⁶,and R⁷ are independently chosen from hydrogen and C₅₋₁₀ heteroaryl.

In certain embodiments of a compound of Formula (I), R², R³, R⁴, R⁵, R⁶,and R⁷ are independently chosen from hydrogen; furyl; imidazol-yl;indol-yl; isoxazol-yl; oxazol-yl; pyrazin-yl; pyridyl; pyrimidin-yl;pyrrol-yl; tetrazol-yl; thienyl; and triazol-yl.

In certain embodiments of a compound of Formula (I), R², R³, R⁴, R⁵, R⁶,and R⁷ are independently chosen from hydrogen; 2-furyl; 3-furyl;1H-imidazol-2-yl; 1H-imidazol-4-yl; 1H-indol-2-yl; 1H-indol-3-yl;1H-indol-4-yl; 1H-indol-5-yl; 1H-indol-6-yl; 1H-indol-7-yl;isoxazol-3-yl; isoxazol-4-yl; isoxazol-5-yl; oxazol-2-yl; oxazol-4-yl;oxazol-5-yl; pyrazin-2-yl; 2-pyridyl; 3-pyridyl; 4-pyridyl;pyrimidin-2-yl; pyrimidin-4-yl; pyrimidin-5-yl; 1H-pyrrol-2-yl;1H-pyrrol-3-yl; 2H-pyrrol-2-yl; 2H-pyrrol-3-yl; 1H-tetrazol-5-yl;2-thienyl; 3-thienyl; 1H-triazol-4-yl; and 4H-1,2,4-triazol-3-yl.

In certain embodiments of a compound of Formula (I), R², R³, R⁴, R⁵, R⁶,and R⁷ are independently chosen from hydrogen; benzimidazol-1-yl;benzotriazol-1-yl; 1,2,4-benzoxadiazin-2-yl; 1,4-benzoxazin-4-yl;carbazol-9-yl; imidazol-1-yl; indazol-1-yl; indolin-1-yl; indol-1-yl;isoindolin-2-yl; phenoxazin-10-yl; purin-7-yl; purin-9-yl; pyrazol-1-yl;pyrrol-1-yl; tetrazol-1-yl; triazol-1-yl; and 1,2,4-triazol-4-yl.

In certain embodiments of a compound of Formula (I), R², R³, R⁴, R⁵, R⁶,and R⁷ are independently chosen from hydrogen; indol-1-yl; purin-7-yl;purin-9-yl; and 1,2,4-triazol-4-yl.

In certain embodiments of a compound of Formula (I), W¹ and W² arechosen from a compound of Formula (I-a) and Formula (I-b).

In certain embodiments of a compound of Formula (I), W¹ and W² are thecompound of Formula (I-a), wherein R³, R⁴, and R⁵ are independentlychosen from hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclohexyl,phenyl, and benzyl; and Y¹ is chosen from a bond and —O—.

In certain embodiments of a compound of Formula (I), W¹ and W² are thecompound of Formula (I-a), wherein R³, R⁴, and R⁵ are independentlychosen from hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclohexyl,phenyl, and benzyl; and Y¹ is a bond.

In certain embodiments of a compound of Formula (I), W¹ and W² are thecompound of Formula (I-a), wherein R³ is chosen from methyl, ethyl,isopropyl, tert-butyl, cyclohexyl, phenyl, and benzyl; R⁴ and R⁵ arechosen from hydrogen and methyl; and Y¹ is a bond.

In certain embodiments of a compound of Formula (I), W¹ and W² are thecompound of Formula (I-a), wherein R³ is chosen from methyl, ethyl,isopropyl, tert-butyl, cyclohexyl, phenyl, and benzyl; R⁴ and R⁵ arehydrogen; and Y¹ is a bond.

In certain embodiments of a compound of Formula (I), W¹ and W² are thecompound of Formula (I-a), wherein R³ is methyl, R⁴ and R⁵ are hydrogen,and Y¹ is a bond.

In certain embodiments of a compound of Formula (I), W¹ and W² are thecompound of Formula (I-a), wherein R³ is ethyl, R⁴ and R⁵ are hydrogen,and Y¹ is a bond.

In certain embodiments of a compound of Formula (I), W¹ and W² are thecompound of Formula (I-a), wherein R³ is isopropyl, R⁴ and R⁵ arehydrogen, and Y¹ is a bond.

In certain embodiments of a compound of Formula (I), W¹ and W² are thecompound of Formula (I-a), wherein R³ is tert-butyl, R⁴ and R⁵ arehydrogen, and Y¹ is a bond.

In certain embodiments of a compound of Formula (I), W¹ and W² are thecompound of Formula (I-a), wherein R³ is cyclohexyl, R⁴ and R⁵ arehydrogen, and Y¹ is a bond.

In certain embodiments of a compound of Formula (I), W¹ and W² are thecompound of Formula (I-a), wherein R³ is phenyl, R⁴ and R⁵ are hydrogen,and Y¹ is a bond.

In certain embodiments of a compound of Formula (I), W¹ and W² are thecompound of Formula (I-a), wherein R³ is benzyl, R⁴ and R⁵ are hydrogen,and Y¹ is a bond.

In certain embodiments of a compound of Formula (I), W¹ and W² are thecompound of Formula (I-b), wherein R⁶ is chosen from methyl, ethyl,isopropyl, tert-butyl, cyclohexyl, phenyl, and benzyl.

In certain embodiments of a compound of Formula (I), W¹ and W² are thecompound of Formula (I-b), wherein R⁶ is methyl.

In certain embodiments of a compound of Formula (I), W² is chosen fromhydrogen and the compound of Formula (I-c).

In certain embodiments of a compound of Formula (I), W² is hydrogen.

In certain embodiments of a compound of Formula (I), W² is the compoundof Formula (I-c), wherein R⁷ is chosen from methyl, ethyl, isopropyl,tert-butyl, cyclohexyl, phenyl, and benzyl.

In certain embodiments of a compound of Formula (I), W² is the compoundof Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), W² is the compoundof Formula (I-c), wherein R⁷ is ethyl.

In certain embodiments of a compound of Formula (I), W² is the compoundof Formula (I-c), wherein R⁷ is isopropyl.

In certain embodiments of a compound of Formula (I), W² is the compoundof Formula (I-c), wherein R⁷ is phenyl.

In certain embodiments of a compound of Formula (I), W² is the compoundof Formula (I-c), wherein R⁷ is benzyl.

In certain embodiments of a compound of Formula (I), each R¹ is chosenfrom hydrogen and methyl; R² is chosen from hydrogen, methyl, ethyl,n-propyl, isopropyl, tert-butyl, cyclohexyl, phenyl, and benzyl; W¹ ischosen from the compound of Formula (I-a) and Formula (I-b); and W² ischosen from hydrogen and the compound of Formula (I-a), Formula (I-b),and Formula (I-c).

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is methyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² is thecompound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is ethyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² is thecompound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is n-propyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² is thecompound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is isopropyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² is thecompound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is n-butyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² is thecompound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is tert-butyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² isthe compound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is cyclohexyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² isthe compound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is phenyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² is thecompound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is benzyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² is thecompound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is methyl, R⁴ is hydrogen, R⁵ is methyl, and Y¹ is a bond; and W² isthe compound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is ethyl, R⁴ is hydrogen, R⁵ is methyl, and Y¹ is a bond; and W² isthe compound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is n-propyl, R⁴ is hydrogen, R⁵ is methyl, and Y¹ is a bond; and W²is the compound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is isopropyl, R⁴ is hydrogen, R⁵ is methyl, and Y¹ is a bond; and W²is the compound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is n-butyl, R⁴ is hydrogen, R⁵ is methyl, and Y¹ is a bond; and W² isthe compound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is tert-butyl, R⁴ is hydrogen, R⁵ is methyl, and Y¹ is a bond; and W²is the compound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is cyclohexyl, R⁴ is hydrogen, R⁵ is methyl, and Y¹ is a bond; and W²is the compound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is phenyl, R⁴ is hydrogen, R⁵ is methyl, and Y¹ is a bond; and W² isthe compound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is benzyl, R⁴ is hydrogen, R⁵ is methyl, and Y¹ is a bond; and W² isthe compound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is methyl, R⁴ is methyl, R⁵ is hydrogen, and Y¹ is a bond; and W² isthe compound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is ethyl, R⁴ is methyl, R⁵ is hydrogen, and Y¹ is a bond; and W² isthe compound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is n-propyl, R⁴ is methyl, R⁵ is hydrogen, and Y¹ is a bond; and W²is the compound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is isopropyl, R⁴ is methyl, R⁵ is hydrogen, and Y¹ is a bond; and W²is the compound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is n-butyl, R⁴ is methyl, R⁵ is hydrogen, and Y¹ is a bond; and W² isthe compound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is tert-butyl, R⁴ is methyl, R⁵ is hydrogen, and Y¹ is a bond; and W²is the compound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is cyclohexyl, R⁴ is methyl, R⁵ is hydrogen, and Y¹ is a bond; and W²is the compound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is phenyl, R⁴ is methyl, R⁵ is hydrogen, and Y¹ is a bond; and W² isthe compound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is benzyl, R⁴ is methyl, R⁵ is hydrogen, and Y¹ is a bond; and W² isthe compound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), the compound ischosen from a compound of Formula (I-A-1), Formula (I-A-2), Formula(I-A-3), Formula (I-A-4), Formula (I-A-5), Formula (I-A-6), Formula(I-A-7), Formula (I-A-8), Formula (I-A-9), Formula (I-A-10), Formula(I-A-11), Formula (I-A-12), Formula (I-A-13), Formula (I-A-14), Formula(I-A-15), Formula (I-A-16), Formula (I-A-17), Formula (I-A-18), Formula(I-A-19), Formula (I-A-20), Formula (I-A-21), Formula (I-A-22), Formula(I-A-23), Formula (I-A-24), Formula (I-A-25), Formula (I-A-26), Formula(I-A-27), Formula (I-A-28), Formula (I-A-29), and Formula (I-A-30), or apharmaceutically acceptable salt of any of the foregoing:

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; and W¹ and W² are the compound of Formula(I-a), wherein R³ is methyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; and W¹ and W² are the compound of Formula(I-a), wherein R³ is ethyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; and W¹ and W² are the compound of Formula(I-a), wherein R³ is isopropyl, R⁴ and R⁵ are hydrogen, and Y¹ is abond.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; and W¹ and W² are the compound of Formula(I-a), wherein R³ is tert-butyl, R⁴ and R⁵ are hydrogen, and Y¹ is abond.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; and W¹ and W² are the compound of Formula(I-a), wherein R³ is cyclohexyl, R⁴ and R⁵ are hydrogen, and Y¹ is abond.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; and W¹ and W² are the compound of Formula(I-a), wherein R³ is phenyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond.

In certain embodiments of a compound of Formula (I), the compound ischosen from a compound of Formula (I-B-1), Formula (I-B-2), Formula(I-B-3), Formula (I-B-4), and Formula (I-B-5), or a pharmaceuticallyacceptable salt of any of the foregoing:

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is ethyl; and W¹ and W² are the compound of Formula (I-a),wherein R³ is methyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is ethyl; and W¹ and W² are the compound of Formula (I-a),wherein R³ is ethyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is ethyl; and W¹ and W² are the compound of Formula (I-a),wherein R³ is isopropyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is ethyl; and W¹ and W² are the compound of Formula (I-a),wherein R³ is tert-butyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is ethyl; and W¹ and W² are the compound of Formula (I-a),wherein R³ is cyclohexyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is ethyl; and W¹ and W² are the compound of Formula (I-a),wherein R³ is phenyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond.

In certain embodiments of a compound of Formula (I), the compound ischosen from a compound of Formula (I-C-1), Formula (I-C-2), Formula(I-C-3), Formula (I-C-4), Formula (I-C-5), and Formula (I-C-6), or apharmaceutically acceptable salt of any of the foregoing:

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is ethyl; W¹ is the compound of Formula (I-a), wherein R³is methyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² is hydrogen.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is ethyl; W¹ is the compound of Formula (I-a), wherein R³is ethyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² is hydrogen.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is ethyl; W¹ is the compound of Formula (I-a), wherein R³is isopropyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² ishydrogen.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is ethyl; W¹ is the compound of Formula (I-a), wherein R³is tert-butyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² ishydrogen.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is ethyl; W¹ is the compound of Formula (I-a), wherein R³is cyclohexyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² ishydrogen.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is ethyl; W¹ is the compound of Formula (I-a), wherein R³is phenyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² is hydrogen.

In certain embodiments of a compound of Formula (I), the compound ischosen from a compound of Formula (I-D-1), Formula (I-D-2), Formula(I-D-3), Formula (I-D-4), Formula (I-D-5), and Formula (I-D-6), or apharmaceutically acceptable salt of any of the foregoing:

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is methyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² isisopropyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is ethyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² isisopropyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is isopropyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² isisopropyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is tert-butyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² isisopropyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is cyclohexyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² isisopropyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is phenyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² isisopropyl.

In certain embodiments of a compound of Formula (I), the compound ischosen from a compound of Formula (I-E-1), Formula (I-E-2), Formula(I-E-3), Formula (I-E-4), Formula (I-E-5), and Formula (I-E-6), or apharmaceutically acceptable salt of any of the foregoing:

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is methyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² isphenyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is ethyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² is phenyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is isopropyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² isphenyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is tert-butyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² isphenyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is cyclohexyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² isphenyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-a), whereinR³ is phenyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² isphenyl.

In certain embodiments of a compound of Formula (I), the compound ischosen from a compound of Formula (I-F-1), Formula (I-F-2), Formula(I-F-3), Formula (I-F-4), Formula (I-F-5), and Formula (I-F-6), or apharmaceutically acceptable salt of any of the foregoing:

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is ethyl; W¹ is the compound of Formula (I-a), wherein R³is methyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² is thecompound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is ethyl; W¹ is the compound of Formula (I-a), wherein R³is ethyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² is thecompound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is ethyl; W¹ is the compound of Formula (I-a), wherein R³is n-propyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² is thecompound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is ethyl; W¹ is the compound of Formula (I-a), wherein R³is isopropyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² is thecompound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is ethyl; W¹ is the compound of Formula (I-a), wherein R³is n-butyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² is thecompound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is ethyl; W¹ is the compound of Formula (I-a), wherein R³is tert-butyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² is thecompound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is ethyl; W¹ is the compound of Formula (I-a), wherein R³is cyclohexyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² is thecompound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is ethyl; W¹ is the compound of Formula (I-a), wherein R³is phenyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² is thecompound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), the compound ischosen from a compound of Formula (I-G-1), Formula (I-G-2), Formula(I-G-3), Formula (I-G-4), Formula (I-G-5), and Formula (I-G-6), or apharmaceutically acceptable salt of any of the foregoing:

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-b), whereinR⁶ is methyl; and W² is the compound of Formula (I-c), wherein R⁷ ismethyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is methyl; W¹ is the compound of Formula (I-b), wherein R⁶is methyl; and W² is the compound of Formula (I-c), wherein R⁷ ismethyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is ethyl; W¹ is the compound of Formula (I-b), wherein R⁶is methyl; and W² is the compound of Formula (I-c), wherein R⁷ ismethyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is isopropyl; W¹ is the compound of Formula (I-b), whereinR⁶ is methyl; and W² is the compound of Formula (I-c), wherein R⁷ ismethyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-b), whereinR⁶ is phenyl; and W² is the compound of Formula (I-c), wherein R⁷ ismethyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is methyl; W¹ is the compound of Formula (I-b), wherein R⁶is phenyl; and W² is the compound of Formula (I-c), wherein R⁷ ismethyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is ethyl; W¹ is the compound of Formula (I-b), wherein R⁶is phenyl; and W² is the compound of Formula (I-c), wherein R⁷ ismethyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is isopropyl; W¹ is the compound of Formula (I-b), whereinR⁶ is phenyl; and W² is the compound of Formula (I-c), wherein R⁷ ismethyl.

In certain embodiments of a compound of Formula (I), the compound ischosen from a compound of Formula (I-H-1), Formula (I-H-2), Formula(I-H-3), Formula (I-H-4), Formula (I-H-5), and Formula (I-H-6) or apharmaceutically acceptable salt of any of the foregoing:

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; and each W¹ and W² is the compound of Formula(I-b), wherein R⁶ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is methyl; and each W¹ and W² is the compound of Formula(I-b), wherein R⁶ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is ethyl; and each W¹ and W² is the compound of Formula(I-b), wherein R⁶ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is isopropyl; and each W¹ and W² is the compound of Formula(I-b), wherein R⁶ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; and each W¹ and W² is the compound of Formula(I-b), wherein R⁶ is phenyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is methyl; and each W¹ and W² is the compound of Formula(I-b), wherein R⁶ is phenyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is ethyl; and each W¹ and W² is the compound of Formula(I-b), wherein R⁶ is phenyl.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is isopropyl; and each W¹ and W² is the compound of Formula(I-b), wherein R⁶ is phenyl.

In certain embodiments of a compound of Formula (I), the compound ischosen from a compound of Formula (I-I-1), Formula (I-I-2), Formula(I-I-3), and Formula (I-I-4), or a pharmaceutically acceptable salt ofany of the foregoing:

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-b), whereinR⁶ is methyl; and W² is hydrogen.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is methyl; W¹ is the compound of Formula (I-b), wherein R⁶is methyl; and W² is hydrogen.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is ethyl; W¹ is the compound of Formula (I-b), wherein R⁶is methyl; and W² is hydrogen.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is isopropyl; W¹ is the compound of Formula (I-b), whereinR⁶ is methyl; and W² is hydrogen.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is hydrogen; W¹ is the compound of Formula (I-b), whereinR⁶ is phenyl; and W² is hydrogen.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is methyl; W¹ is the compound of Formula (I-b), wherein R⁶is phenyl; and W² is hydrogen.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is ethyl; W¹ is the compound of Formula (I-b), wherein R⁶is phenyl; and W² is hydrogen.

In certain embodiments of a compound of Formula (I), each R¹ ishydrogen; R² is isopropyl; W¹ is the compound of Formula (I-b), whereinR⁶ is phenyl; and W² is hydrogen.

In certain embodiments of a compound of Formula (I), the compound ischosen from a compound of Formula (I-J-1), Formula (I-J-2), Formula(I-J-3), and Formula (I-J-4), or a pharmaceutically acceptable salt ofany of the foregoing:

In certain embodiments of a compound of Formula (I), each R¹ is methyl;R² is hydrogen; and W¹ and W² are the compound of Formula (I-a), whereinR³ is methyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond.

In certain embodiments of a compound of Formula (I), each R¹ is methyl;R² is hydrogen; and W¹ and W² are the compound of Formula (I-a), whereinR³ is ethyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond.

In certain embodiments of a compound of Formula (I), each R¹ is methyl;R² is hydrogen; and W¹ and W² are the compound of Formula (I-a), whereinR³ is isopropyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond.

In certain embodiments of a compound of Formula (I), each R¹ is methyl;R² is hydrogen; and W¹ and W² are the compound of Formula (I-a), whereinR³ is cyclohexyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond.

In certain embodiments of a compound of Formula (I), each R¹ is methyl;R² is hydrogen; and W¹ and W² are the compound of Formula (I-a), whereinR³ is phenyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond.

In certain embodiments of a compound of Formula (I), the compound ischosen from a compound of Formula (I-AA-1), Formula (I-AA-2), Formula(I-AA-3), Formula (I-AA-4), and Formula (I-AA-5), or a pharmaceuticallyacceptable salt of any of the foregoing:

In certain embodiments of a compound of Formula (I), each R¹ is methyl;R² is hydrogen; W¹ is the compound of Formula (I-a), wherein R³ ismethyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² is hydrogen.

In certain embodiments of a compound of Formula (I), each R¹ is methyl;R² is hydrogen; W¹ is the compound of Formula (I-a), wherein R³ isethyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² is hydrogen.

In certain embodiments of a compound of Formula (I), each R¹ is methyl;R² is hydrogen; W¹ is the compound of Formula (I-a), wherein R³ isisopropyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² is hydrogen.

In certain embodiments of a compound of Formula (I), each R¹ is methyl;R² is hydrogen; W¹ is the compound of Formula (I-a), wherein R³ istert-butyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² ishydrogen.

In certain embodiments of a compound of Formula (I), each R¹ is methyl;R² is hydrogen; W¹ is the compound of Formula (I-a), wherein R³ iscyclohexyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² ishydrogen.

In certain embodiments of a compound of Formula (I), each R¹ is methyl;R² is hydrogen; W¹ is the compound of Formula (I-a), wherein R³ isphenyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² is hydrogen.

In certain embodiments of a compound of Formula (I), the compound ischosen from a compound of Formula (I-BB-1), Formula (I-BB-2), Formula(I-BB-3), Formula (I-BB-4), Formula (I-BB-5), and Formula (I-BB-6), or apharmaceutically acceptable salt of any of the foregoing:

In certain embodiments of a compound of Formula (I), each R¹ is methyl;R² is hydrogen; W¹ is the compound of Formula (I-a), wherein R³ ismethyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² is the compoundof Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ is methyl;R² is hydrogen; W¹ is the compound of Formula (I-a), wherein R³ isethyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² is the compoundof Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ is methyl;R² is hydrogen; W¹ is the compound of Formula (I-a), wherein R³ isisopropyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² is thecompound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ is methyl;R² is hydrogen; W¹ is the compound of Formula (I-a), wherein R³ istert-butyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² is thecompound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ is methyl;R² is hydrogen; W¹ is the compound of Formula (I-a), wherein R³ iscyclohexyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² is thecompound of Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ is methyl;R² is hydrogen; W¹ is the compound of Formula (I-a), wherein R³ isphenyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond; and W² is the compoundof Formula (I-c), wherein R⁷ is methyl.

In certain embodiments of a compound of Formula (I), the compound ischosen from a compound of Formula (I-CC-1), Formula (I-CC-2), Formula(I-CC-3), Formula (I-CC-4), Formula (I-CC-5), and Formula (I-CC-6), or apharmaceutically acceptable salt of any of the foregoing:

In certain embodiments of a compound of Formula (I), each R¹ is methyl;R² is hydrogen; and W¹ and W² are the compound of Formula (I-b), whereinR⁶ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ is methyl;R² is methyl; and W¹ and W² are the compound of Formula (I-b), whereinR⁶ is methyl.

In certain embodiments of a compound of Formula (I), each R¹ is methyl;R² is ethyl; and W¹ and W² are the compound of Formula (I-b), wherein R⁶is methyl.

In certain embodiments of a compound of Formula (I), each R¹ is methyl;R² is isopropyl; and W¹ and W² are the compound of Formula (I-b),wherein R⁶ is methyl.

In certain embodiments of a compound of Formula (I), the compound ischosen from a compound of Formula (I-DD-1), Formula (I-DD-2), Formula(I-DD-3), and Formula (I-DD-4), or a pharmaceutically acceptable salt ofany of the foregoing:

In certain embodiments of a compound of Formula (I), each R¹ is methyl;R² is hydrogen; W¹ is the compound of Formula (I-b), wherein R⁶ ismethyl; and W² is hydrogen.

In certain embodiments of a compound of Formula (I), each R¹ is methyl;R² is ethyl; W¹ is the compound of Formula (I-b), wherein R⁶ is methyl;and W² is hydrogen.

In certain embodiments of a compound of Formula (I), each R¹ is methyl;R² is isopropyl; W¹ is the compound of Formula (I-b), wherein R⁶ ismethyl; and W² is hydrogen.

In certain embodiments of a compound of Formula (I), the compound ischosen from a compound of Formula (I-EE-1), Formula (I-EE-2), andFormula (I-EE-3), or a pharmaceutically acceptable salt of any of theforegoing:

In certain embodiments of a compound of Formula (I), each R¹ is methyl;R² is hydrogen; W¹ is the compound of Formula (I-b), wherein R⁶ ismethyl; and W² is the compound of Formula (I-a), wherein R³ is methyl,R⁴ and R⁵ are hydrogen, and Y¹ is a bond.

In certain embodiments of a compound of Formula (I), each R¹ is methyl;R² is hydrogen; W¹ is the compound of Formula (I-b), wherein R⁶ ismethyl; and W² is the compound of Formula (I-a), wherein R³ isisopropyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond.

In certain embodiments of a compound of Formula (I), each R¹ is methyl;R² is ethyl; W¹ is the compound of Formula (I-b), wherein R⁶ is methyl;and W² is the compound of Formula (I-a), wherein R³ is isopropyl, R⁴ andR⁵ are hydrogen, and Y¹ is a bond.

In certain embodiments of a compound of Formula (I), each R¹ is methyl;R² is isopropyl; W¹ is the compound of Formula (I-b), wherein R⁶ ismethyl; and W² is the compound of Formula (I-a), wherein R³ isisopropyl, R⁴ and R⁵ are hydrogen, and Y¹ is a bond.

In certain embodiments of a compound of Formula (I), the compound ischosen from a compound of Formula (I-FF-1), Formula (I-FF-2), andFormula (I-FF-3), or a pharmaceutically acceptable salt of any of theforegoing:

Synthesis

Compounds disclosed herein may be obtained via the synthetic methodsillustrated in Schemes I-A to I-F. General synthetic methods useful inthe synthesis of compounds described herein are available in the art.Starting materials useful for preparing compounds and intermediatesthereof and/or practicing methods described herein are commerciallyavailable or can be prepared by well-known synthetic methods. Themethods presented in the schemes provided by the present disclosure areillustrative rather than comprehensive. It will be apparent to thoseskilled in the art that many modifications, both to materials andmethods, may be practiced without departing from the scope of thedisclosure.

Compounds of Formula (I) can be prepared according to Schemes I-A toI-F:

Pharmaceutical Compositions

Pharmaceutical compositions provided by the present disclosure maycomprise a therapeutically effective amount of a compound of Formula (I)together with a suitable amount of one or more pharmaceuticallyacceptable vehicles so as to provide a composition for properadministration to a patient. Suitable pharmaceutical vehicles aredescribed in the art.

In certain embodiments, a compound of Formula (I) may be incorporatedinto pharmaceutical compositions to be administered orally. Oraladministration of such pharmaceutical compositions may result in uptakeof a compound of Formula (I) throughout the intestine and entry into thesystemic circulation. Such oral compositions may be prepared in a mannerknown in the pharmaceutical art and comprise a compound of Formula (I)and at least one pharmaceutically acceptable vehicle. Oralpharmaceutical compositions may include a therapeutically effectiveamount of a compound of Formula (I) and a suitable amount of apharmaceutically acceptable vehicle, so as to provide an appropriateform for administration to a patient.

Compounds of Formula (I) may be incorporated into pharmaceuticalcompositions to be administered by any other appropriate route ofadministration including intradermal, intramuscular, intraperitoneal,intravenous, subcutaneous, intranasal, epidural, oral, sublingual,intracerebral, intravaginal, transdermal, rectal, inhalation, ortopical.

Pharmaceutical compositions comprising a compound of Formula (I) and maybe manufactured by means of conventional mixing, dissolving,granulating, dragee-making, levigating, emulsifying, encapsulating,entrapping, or lyophilizing processes. Pharmaceutical compositions maybe formulated in a conventional manner using one or more physiologicallyacceptable carriers, diluents, excipients, or auxiliaries, whichfacilitate processing of compounds of Formula (I) or crystalline formsthereof and one or more pharmaceutically acceptable vehicles intoformulations that can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen. Pharmaceuticalcompositions provided by the present disclosure may take the form ofsolutions, suspensions, emulsion, tablets, pills, pellets, capsules,capsules containing liquids, powders, sustained-release formulations,suppositories, emulsions, aerosols, sprays, suspensions, or any otherform suitable for administration to a patient.

Pharmaceutical compositions provided by the present disclosure may beformulated in a unit dosage form. A unit dosage form refers to aphysically discrete unit suitable as a unitary dose for patientsundergoing treatment, with each unit containing a predetermined quantityof a compound of Formula (I) calculated to produce an intendedtherapeutic effect. A unit dosage form may be for a single daily dose,for administration 2 times per day, or one of multiple daily doses,e.g., 3 or more times per day. When multiple daily doses are used, aunit dosage form may be the same or different for each dose. One or moredosage forms may comprise a dose, which may be administered to a patientat a single point in time or during a time interval.

Pharmaceutical compositions comprising a compound of Formula (I) may beformulated for immediate release.

In certain embodiments, an oral dosage form provided by the presentdisclosure may be a controlled release dosage form. Controlled deliverytechnologies can improve the absorption of a drug in a particular regionor regions of the gastrointestinal tract. Controlled drug deliverysystems may be designed to deliver a drug in such a way that the druglevel is maintained within a therapeutically effective window andeffective and safe blood levels are maintained for a period as long asthe system continues to deliver the drug with a particular releaseprofile in the gastrointestinal tract. Controlled drug delivery mayproduce substantially constant blood levels of a drug over a period oftime as compared to fluctuations observed with immediate release dosageforms. For some drugs, maintaining a constant blood and tissueconcentration throughout the course of therapy is the most desirablemode of treatment. Immediate release of drugs may cause blood levels topeak above the level required to elicit a desired response, which maywaste the drug and may cause or exacerbate toxic side effects.Controlled drug delivery can result in optimum therapy, and not only canreduce the frequency of dosing, but may also reduce the severity of sideeffects. Examples of controlled release dosage forms include dissolutioncontrolled systems, diffusion controlled systems, ion exchange resins,osmotically controlled systems, erodable matrix systems, pH independentformulations, gastric retention systems, and the like.

An appropriate oral dosage form for a particular pharmaceuticalcomposition provided by the present disclosure may depend, at least inpart, on the gastrointestinal absorption properties of a compound ofFormula (I) the stability of a compound of Formula (I) in thegastrointestinal tract, the pharmacokinetics of a compound of Formula(I) and the intended therapeutic profile. An appropriate controlledrelease oral dosage form may be selected for a particular compound ofFormula (I). For example, gastric retention oral dosage forms may beappropriate for compounds absorbed primarily from the uppergastrointestinal tract, and sustained release oral dosage forms may beappropriate for compounds absorbed primarily from the lowergastrointestinal tract. Certain compounds are absorbed primarily fromthe small intestine. In general, compounds traverse the length of thesmall intestine in about 3 to 5 hours. For compounds that are not easilyabsorbed by the small intestine or that do not dissolve readily, thewindow for active agent absorption in the small intestine may be tooshort to provide a desired therapeutic effect.

In certain embodiments, pharmaceutical compositions provided by thepresent disclosure may be practiced with dosage forms adapted to providesustained release of a compound of Formula (I) upon oral administration.Sustained release oral dosage forms may be used to release drugs over aprolonged time period and are useful when it is desired that a drug ordrug form be delivered to the lower gastrointestinal tract. Sustainedrelease oral dosage forms include any oral dosage form that maintainstherapeutic concentrations of a drug in a biological fluid such as theplasma, blood, cerebrospinal fluid, or in a tissue or organ for aprolonged time period. Sustained release oral dosage forms includediffusion-controlled systems such as reservoir devices and matrixdevices, dissolution-controlled systems, osmotic systems, anderosion-controlled systems. Sustained release oral dosage forms andmethods of preparing the same are well known in the art.

An appropriate dose of a compound of Formula (I) or pharmaceuticalcomposition comprising a compound of Formula (I) may be determinedaccording to any one of several well-established protocols. For example,animal studies such as studies using mice, rats, dogs, and/or monkeysmay be used to determine an appropriate dose of a pharmaceuticalcompound. Results from animal studies may be extrapolated to determinedoses for use in other species, such as for example, humans.

Uses

Compounds of Formula (I) and pharmaceutical compositions thereof may beadministered to a patient suffering from any disease including adisorder, condition, or symptom for which L-cysteine,N-acetyl-L-cysteine, or D-penicillamine are known or hereafterdiscovered to be therapeutically effective. Indications for whichL-cysteine, N-acetyl-L-cysteine, or D-penicillamine have beenprescribed, and hence for which a compound of Formula (I), orpharmaceutical compositions thereof are also expected to be effective,include chronic bronchopulmonary disease, acetaminophen overdose,Wilson's disease, cystinuria, and rheumatoid arthritis. Otherindications for which compounds of Formula (I) may be therapeuticallyeffective include austism, Gaucher's disease, cystic fibrosis,Parkinson's disease, multiple sclerosis, inflammatory bowel disease, andasthma.

Methods of treating a disease in a patient provided by the presentdisclosure comprise administering to a patient in need of such treatmenta therapeutically effective amount of a compound of Formula (I).Compounds of Formula (I) or pharmaceutical compositions thereof mayprovide therapeutic or prophylactic plasma and/or blood concentrationsof L-cysteine, N-acetyl-L-cysteine, or D-penicillamine followingadministration to a patient.

Compounds of Formula (I) may be included in a pharmaceutical compositionand/or dosage form adapted for oral administration, although compound ofFormula (I) may also be administered by any other appropriate route,such as for example, by injection, infusion, inhalation, transdermal, orabsorption through epithelial or mucosal membranes (e.g., oral, rectal,and/or intestinal mucosa).

Compounds of Formula (I) may be administered in an amount and using adosing schedule as appropriate for treatment of a particular disease.Daily doses of a compound of Formula (I) may range from about 0.01 mg/kgto about 500 mg/kg, from about 0.1 mg/kg to about 200 mg/kg, from about1 mg/kg to about 50 mg/kg, and in certain embodiments, from about 5mg/kg to about 25 mg/kg. In certain embodiments, compounds of Formula(I) may be administered at a dose over time from about 1 mg to about 20g per day, from about 10 mg to about 10 g per day, and in certainembodiments from about 20 mg to about 5 g per day. An appropriate doseof a compound of Formula (I) may be determined based on several factors,including, for example, the body weight and/or condition of the patientbeing treated, the severity of the disease being treated, the incidenceand/or severity of side effects, the manner of administration, and thejudgment of the prescribing physician. Appropriate dose ranges may bedetermined by methods known to those skilled in the art.

Compounds of Formula (I) may be assayed in vitro and in vivo for thedesired therapeutic or prophylactic activity prior to use in humans. Invivo assays, for example using appropriate animal models, may also beused to determine whether administration of a compound of Formula (I) istherapeutically effective.

In certain embodiments, a therapeutically effective dose of a compoundof Formula (I) may provide therapeutic benefit without causingsubstantial toxicity including adverse side effects. Toxicity ofcompounds of Formula (I) and/or metabolites thereof may be determinedusing standard pharmaceutical procedures and may be ascertained by thoseskilled in the art. The dose ratio between toxic and therapeutic effectis the therapeutic index. A dose of a compound of Formula (I) may bewithin a range capable of establishing and maintaining a therapeuticallyeffective circulating plasma and/or blood concentration of a compound ofFormula (I) that exhibits little or no toxicity

L-cysteine, N-acetyl-L-cysteine, or D-penicillamine prodrug of Formula(I) may be used to treat diseases, disorders, conditions, and symptomsof any of the foregoing for which L-cysteine, N-acetyl-L-cysteine, orD-penicillamine is known to provide or is later found to providetherapeutic benefit. L-cysteine, N-acetyl-L-cysteine, or D-penicillamineis known to be effective in treating chronic bronchopulmonary disease,acetaminophen overdose, Wilson's disease, cystinuria, and rheumatoidarthritis. Hence, compounds of Formula (I) may be used to treat any ofthe foregoing diseases and disorders. The underlying etiology of any ofthe foregoing diseases being treated may have a multiplicity of origins.Further, in certain embodiments, a therapeutically effective amount ofone or more compounds of Formula (I) may be administered to a patient,such as a human, as a preventative measure against various diseases ordisorders.

Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD), also known as chronicobstructive airway disease, is a group of diseases characterized by thepathological limitation of airflow in the airway that is not fullyreversible, and includes conditions such as chronic bronchitis,emphysema, as well as other lung disorders such as asbestosis,pneumoconiosis, and pulmonary neoplasms (see, e.g., Barnes,Pharmacological Reviews 2004, 56(4), 515-548). The airflow limitation isusually progressive and associated with an abnormal inflammatoryresponse of the lungs to noxious particles and gases. COPD ischaracterized by a shortness of breath the last for months or years,possibly accompanied by wheezing, and a persistent cough with sputumproduction. COPD is most often caused by tobacco smoking, although itcan also be caused by other airborne irritants such as coal dust,asbestos, urban pollution, or solvents. COPD encompasses chronicobstructive bronchiolitis with fibrosis and obstruction of smallairways, and emphysema with enlargement of airspaces and destruction oflung parenchyma, loss of lung elasticity, and closure of small airways.

The efficacy of administering at least one compound of Formula (I) fortreating chronic obstructive pulmonary disease may be assessed usinganimal models of chronic obstructive pulmonary disease and in clinicalstudies. For example, murine models of chronic obstructive pulmonarydisease are known. Furthermore, in a clinical study NAC was found toimprove small airways function and decrease exacerbation frequency inpatients with stable COPD (Tse, Chest 2013, 144(1), 106-118).

Paracetamol Overdose

Excessive paracetamol intake is known to generate hepatotoxic metaboliteN-acetyl-p-benzoquinone imine. NAC is currently being used to treatparacetamol overdose.

The efficacy of NAC prodrugs of Formula (I) for paracetamol overdose maybe assessed using animal and human models of paracetamol poisoning andin clinical studies.

Wilson's Disease

Wilson's disease is a genetic disease in which copper accumulates inliver and brain. The disorder is characterized by tiredness, increasedbleeding tendency or confusion (due to hepatic encephalopathy), portalhypertension, mild cognitive deterioration, bradykinesia, dystonia,seizures and migraine.

The efficacy of D-penicillamine-related compounds of Formula (I) fortreating Wilson's disease can be determined using animal models and inclinical trials.

Cystinuria

Cystinuria is a genetic disease in which cystine is inadequatereabsorped in the proximal convoluted tubules, resulting in cystinestones in the kidneys, ureter, and bladder.

Efficacy of D-penicillamine-related compounds of Formula (I) fortreating Cystinuria can be determined using animal models and inclinical trials.

Rheumatoid Arthritis

Rheumatoid arthritis is a chronic inflammatory disorder that typicallyaffects the lining of small joints in hands and feet, causing painfulswelling that can eventually result in bone erosion and joint deformity.

Efficacy of D-penicillamine-related compounds of Formula (I) fortreating rheumatoid arthritis can be determined using animal models andin clinical trials.

Autism Spectrum Disorder

Autism spectrum disorder is characterized by social deficits andcommunication difficulties, stereotyped or repetitive behaviors andinterests, sensory issues, and in some cases, cognitive delays.

Efficacy of cysteine-related compounds of Formula (I) for treatingautism spectrum disorder can be determined using animal models and inclinical trials.

Gaucher's Disease

Gaucher's disease is a genetic disease in which fatty substances(sphingolipids) accumulate in cells and certain organs. The disorder ischaracterized by bruising, fatigue, anemia, low blood platelets, andenlargement of the liver and spleen.

Efficacy of cysteine-related compounds of Formula (I) for treatingGaucher's disease can be determined using animal models and in clinicaltrials.

Cystic Fibrosis

Cystic fibrosis is a life-threatening genetic disorder that causessevere damage to the lungs and digestive system. High dose oralN-acetylcysteine is thought to modulate inflammation in cystic fibrosis(Tirouvanziam et al., Proc. Natl. Acad. Sci. 2006, 103 (12), 4628-33).

The efficacy of compounds of Formula (I) for cystic fibrosis may beassessed using animal and human models of cytic fibrosis and in clinicalstudies.

Parkinson's Disease

Parkinson's disease is a slowly progressive degenerative disorder of thenervous system characterized by tremor when muscles are at rest (restingtremor), slowness of voluntary movements, and increased muscle tone(rigidity). In Parkinson's disease, nerve cells in the basal ganglia,e.g., substantia nigra, degenerate, and thereby reduce the production ofdopamine and the number of connections between nerve cells in the basalganglia. As a result, the basal ganglia are unable to smooth musclemovements and coordinate changes in posture as normal, leading totremor, incoordination, and slowed, reduced movement (bradykinesia)(Blandini, et al., Mol. Neurobiol. 1996, 12, 73-94).

The efficacy of compounds of Formula (I) for treating Parkinson'sdisease may be assessed using animal and human models of Parkinson'sdisease and in clinical studies.

Multiple Sclerosis

Multiple sclerosis (MS) is an inflammatory autoimmune disease of thecentral nervous system caused by an autoimmune attack against theisolating axonal myelin sheets of the central nervous system.Demyelination leads to the breakdown of conduction and to severe diseasewith destruction of local axons and irreversible neuronal cell death.The symptoms of MS are highly varied with each individual patientexhibiting a particular pattern of motor, sensible, and sensorydisturbances. MS is typified pathologically by multiple inflammatoryfoci, plaques of demyelination, gliosis, and axonal pathology within thebrain and spinal cord, all of which contribute to the clinicalmanifestations of neurological disability (see e.g., Wingerchuk, LabInvest 2001, 81, 263-281; and Virley, NeuroRx 2005, 2(4), 638-649).Although the causal events that precipitate MS are not fully understood,evidence implicates an autoimmune etiology together with environmentalfactors, as well as specific genetic predispositions. Functionalimpairment, disability, and handicap are expressed as paralysis, sensoryand octintive disturbances spasticity, tremor, a lack of coordination,and visual impairment, which impact on the quality of life of theindividual. The clinical course of MS can vary from individual toindividual, but invariably the disease can be categorized in threeforms: relapsing-remitting, secondary progressive, and primaryprogressive.

Assessment of MS treatment efficacy using cysteine-related compounds ofFormula (I) in clinical trials can be accomplished using tools such asthe Expanded Disability Status Scale and the MS Functional as well asmagnetic resonance imaging lesion load, biomarkers, and self-reportedquality of life. Animal models of MS shown to be useful to identify andvalidate potential therapeutics include experimental autoimmune/allergicencephalomyelitis (EAE) rodent models that simulate the clinical andpathological manifestations of MS and nonhuman primate EAE models.

Inflammatory Bowel Disease (Crohn's Disease, Ulcerative Colitis)

Inflammatory bowel disease (IBD) is a group of inflammatory conditionsof the large intestine and in some cases, the small intestine thatincludes Crohn's disease and ulcerative colitis. Crohn's disease, whichis characterized by areas of inflammation with areas of normal lining inbetween, can affect any part of the gastrointestinal tract from themouth to the anus. The main gastrointestinal symptoms are abdominalpain, diarrhea, constipation, vomiting, weight loss, and/or weight gain.Crohn's disease can also cause skin rashes, arthritis, and inflammationof the eye. Ulcerative colitis is characterized by ulcers or open soresin the large intestine or colon. The main symptom of ulcerative colitisis typically constant diarrhea with mixed blood of gradual onset. Othertypes of intestinal bowel disease include collagenous colitis,lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet'scolitis, and indeterminate colitis.

The efficacy of cysteine-related compounds for treating inflammatorybowel disease can be evaluated using animal models and in clinicaltrials. Useful animal models of inflammatory bowel disease are known.

Asthma

Asthma is reversible airway obstruction in which the airway occasionallyconstricts, becomes inflamed, and is lined with an excessive amount ofmucus. Symptoms of asthma include dyspnea, wheezing, chest tightness,and cough. Asthma episodes may be induced by airborne allergens, foodallergies, medications, inhaled irritants, physical exercise,respiratory infection, psychological stress, hormonal changes, coldweather, or other factors.

The efficacy of compounds of Formula (I) for treating asthma can beassessed using animal models and in clinical trials.

Interstitial Lung Disease

Interstitial lung disease (ILD), also known as diffuse parenchymal lungdisease (DPLD), refers to a group of lung diseases affecting theinterstitium. The term idiopathic pulmonary fibrosis is used to describeinterstitial lung disease for which no obvious cause can be identified.

The efficacy of compounds of Formula (I) for treating interstitial lungdisease can be assessed using animal models and in clinical trials.

Psychiatric Disorders

According to Diagnostic and Statistical Manual of Mental Disorders IV, amental or psychiatric disorder is a psychological syndrome or pattern,which occurs in an individual, and causes distress via a painful symptomor disability, or increases the risk of death, pain, or disability.Psychiatric disorder such as addiction, compulsive and groomingdisorders, schizophrenia and bipolar disorder may be treated withN-acetylcysteine (Dean et al., Journal of psychiatry & neuroscience2011, 36 (2), 78-86).

The efficacy of compounds of Formula (I) for treating psychiatricdisorders may be assessed using animal models and in clinical trials.

Administration

Compounds of Formula (I) and pharmaceutical compositions thereof may beadministered orally or by any other appropriate route, for example, byinfusion or bolus injection, by absorption through epithelial ormucocutaneous linings (e.g., oral mucosa, rectal, and intestinal mucosa,etc.). Other suitable routes of administration include, but are notlimited to, intradermal, intramuscular, intraperitoneal, intravenous,subcutaneous, intranasal, epidural, oral, sublingual, intracerebral,intravaginal, transdermal, rectal, inhalation, or topical.

Administration may be systemic or local. Various delivery systems areknown, e.g., encapsulation in liposomes, microparticles, microcapsules,capsules, etc.) that may be used to administer a compound and/orpharmaceutical composition.

The amount of a compound of Formula (I) that will be effective in thetreatment of a disease in a patient will depend, in part, on the natureof the condition and can be determined by standard clinical techniquesknown in the art. In addition, in vitro or in vivo assays may beemployed to help identify optimal dosage ranges. A therapeuticallyeffective amount of a compound of Formula (I) to be administered mayalso depend on, among other factors, the subject being treated, theweight of the subject, the severity of the disease, the manner ofadministration, and the judgment of the prescribing physician.

For systemic administration, a therapeutically effective dose may beestimated initially from in vitro assays. For example, a dose may beformulated in animal models to achieve a beneficial circulatingcomposition concentration range. Initial doses may also be estimatedfrom in vivo data, e.g., animal models, using techniques that are knownin the art. Such information may be used to more accurately determineuseful doses in humans. One having ordinary skill in the art mayoptimize administration to humans based on animal data.

A dose may be administered in a single dosage form or in multiple dosageforms. When multiple dosage forms are used the amount of compoundcontained within each dosage form may be the same or different. Theamount of a compound of Formula (I) contained in a dose may depend onthe route of administration and whether the disease in a patient iseffectively treated by acute, chronic, or a combination of acute andchronic administration.

In certain embodiments an administered dose is less than a toxic dose.Toxicity of the compositions described herein may be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., by determining the LD50 (the dose lethal to 50% of thepopulation) or the LD100 (the dose lethal to 100% of the population).The dose ratio between toxic and therapeutic effect is the therapeuticindex. In certain embodiments, a cysteine-related compound may exhibit ahigh therapeutic index. The data obtained from these cell culture assaysand animal studies may be used in formulating a dosage range that is nottoxic for use in humans. A dose of a cysteine-related compound providedby the present disclosure may be within a range of circulatingconcentrations in for example the blood, plasma, or central nervoussystem, that include the effective dose and that exhibits little or notoxicity. A dose may vary within this range depending upon the dosageform employed and the route of administration utilized. In certainembodiments, an escalating dose may be administered.

Combination Therapy

Methods provided by the present disclosure further compriseadministering one or more pharmaceutically active compounds in additionto a compound of Formula (I). Such compounds may be provided to treatthe same disease or a different disease than the disease being treatedwith the L-cysteine, N-acetyl-L-cysteine, or D-penicillamine prodrug ofFormula (I).

In certain embodiments, a compound of Formula (I) may be used incombination with at least one other therapeutic agent. In certainembodiments, a compound of Formula (I) may be administered to a patienttogether with another compound for treating diseases and conditionsinvolving immunological, autoimmune, and/or inflammatory processesincluding: psoriasis; asthma, chronic obstructive pulmonary diseases,and arthritis; cardiac insufficiency including left ventricularinsufficiency, myocardial infarction and angina pectoris; mitochondrialand neurodegenerative diseases such as Parkinson's disease, Alzheimer'sdisease, Huntington's disease, retinopathia pigmentosa and mitochondrialencephalomyopathy; transplantation rejection; autoimmune diseasesincluding multiple sclerosis (MS); ischemia and reperfusion injury(AGE-induced genome damage; and others. In certain embodiments, acompound of Formula (I) may be administered to a patient together withanother compound for treating psoriasis, multiple sclerosis, aninflammatory bowel disease, asthma, chronic obstructive pulmonarydisease, and arthritis.

A compound of Formula (I) and the at least one other therapeutic agentmay act additively or, and in certain embodiments, synergistically. Theat least one additional therapeutic agent may be included in the samedosage form as a compound of Formula (I) or may be provided in aseparate dosage form. Methods provided by the present disclosure canfurther include, in addition to administering a compound of Formula (I),administering one or more therapeutic agents effective for treating thesame or different disease than the disease being treated by a compoundof Formula (I). Methods provided by the present disclosure includeadministration of a compound of Formula (I) and one or more othertherapeutic agents provided that the combined administration does notinhibit the therapeutic efficacy of the L-cysteine, N-acetyl-L-cysteine,or D-penicillamine prodrug and/or does not typically produce significantand/or substantial adverse combination effects.

In certain embodiments, dosage forms comprising a compound of Formula(I) may be administered concurrently with the administration of anothertherapeutic agent, which may be part of the same dosage form as, or in adifferent dosage form than that comprising a compound of Formula (I). Acompound of Formula (I) may be administered prior or subsequent toadministration of another therapeutic agent. In certain embodiments ofcombination therapy, the combination therapy may comprise alternatingbetween administering a compound of Formula (I) and a compositioncomprising another therapeutic agent, e.g., to minimize adverse drugeffects associated with a particular drug. When a compound of Formula(I) is administered concurrently with another therapeutic agent thatpotentially may produce an adverse drug effect including, but notlimited to, toxicity, the other therapeutic agent may advantageously beadministered at a dose that falls below the threshold at which theadverse drug reaction is elicited.

In certain embodiments, dosage forms comprising a compound of Formula(I) may be administered with one or more substances to enhance, modulateand/or control release, bioavailability, therapeutic efficacy,therapeutic potency, stability, and the like of a MBF prodrug of Formula(I). For example, to enhance the therapeutic efficacy of acysteine-related compound ligand of Formula (I), the L-cysteine,N-acetyl-L-cysteine, or D-penicillamine prodrug of Formula (I) may beco-administered with or a dosage form comprising a compound of Formula(I) may comprise one or more active agents to increase the absorption ordiffusion of a compound of Formula (I) from the gastrointestinal tractto the systemic circulation, or to inhibit degradation of theL-cysteine, N-acetyl-L-cysteine, or D-penicillamine prodrug of Formula(I) in the blood of a patient. In certain embodiments, a compound ofFormula (I) may be co-administered with an active agent havingpharmacological effects that enhance the therapeutic efficacy of acompound of Formula (I).

In certain embodiments, a compound of Formula (I) or a pharmaceuticalcomposition thereof may be administered to a patient for treatingpsoriasis in combination with a therapy or another therapeutic agentknown or believed to be effective in treating psoriasis. Drugs usefulfor treating psoriasis include steroids such as flurandrenolide,fluocinonide, alclometasone, amcinonide, desonide, halcinonide,triamcinolone, clobetasol, clocortolone, mometasone, desoximetasone, andhalobetasol; anti-rheumatics such as etanercept, infiximab, andadalimumab; immunosuppressive agents such as cyclosporine, alefacept,and efalizumab; psoralens such as methoxsalen; and other such ascalcipotriene, methotrexate, hydrocortisone/pramoxine, acitretin,betamethasone/calcipotriene, tazaraotene, benzocaine/pyrilamine/zincoxide, and ustekinumab.

In certain embodiments, a compound of Formula (I) or a pharmaceuticalcomposition thereof may be administered to a patient for treatinginflammatory arthritis such as rheumatoid arthritis, juvenile rheumatoidarthritis, psoriatic arthritis, and ankylosing spondylitis incombination with a therapy or another therapeutic agent known orbelieved to be effective in treating inflammatory arthritis such asrheumatoid arthritis, juvenile rheumatoid arthritis, psoriaticarthritis, and ankylosing spondylitis.

Drugs useful for treating rheumatoid arthritis include non-steroidalanti-inflammatory agents such as ibuprofen, ketoprofen, salicylate,diclofenac, nabumetone, naproxen, meloxicam, sulindac, flurbiprofen,indomethacin, tolmetin, piroxicam, fenoprofen, oxaprozin, and etodolac;antiheumatics such as entanercept, adalimumab, infliximab,hydroxychloroquine, leflunomide, azathioprine, penicillamine,methotrexate, anakinra, auranofin, rituximab, aurothioglucose,tocilizumab, and golimumab; cox-2 inhibtors such as celecoxib andvadecoxib; corticosteroids such as triamcinolone; glucocorticoids suchas methylprednisolone and prednisone; and others such as sulfasalazine.

Drugs useful for treating juvenile rheumatoid arthritis includeadalimumab, abatacept, and infliximab.

Drugs useful for treating psoriatic arthritis include etanercept,adalimumab, triamcinolone, cortisone, infliximab, and golimumab.

Drugs useful for treating ankylosing spondylitis include adalimumab,celecoxib, diclofenac, etanercept, golimumab, indomethacin infliximab,naptoxen, olsalazine, salicylates, sulfindac, and triamcinolone.

In certain embodiments, a compound of Formula (I) or a pharmaceuticalcomposition thereof may be administered to a patient for treatingpsoriatic arthritis in combination with a therapy or another therapeuticagent known or believed to be effective in treating psioriaticarthritis. Drugs useful for treating psioriatic arthritis includeetanercept, adalimumab, triamcinolone, cortisone, infliximab, andgolimumab.

In certain embodiments, a compound of Formula (I) or a pharmaceuticalcomposition thereof may be administered to a patient for treatingautoimmune diseases such as lupus in combination with a therapy oranother therapeutic agent known or believed to be effective in treatingautoimmune diseases such as lupus. Drugs useful for treating lupusinclude hydroxychlooquine, triamcinolone, salicylate, azathioprine, andabetimus.

In certain embodiments, a compound of Formula (I) or a pharmaceuticalcomposition thereof may be administered to a patient for treatingmultiple sclerosis in combination with a therapy or another therapeuticagent known or believed to be effective in treating multiple sclerosis.Drugs useful for treating multiple sclerosis include interferon β-1a,interferon β-1b, glatiramer, modafinil, azathioprine, predisolone,mycophenolate mofetil, mitoxantrone, and natalizumab. Other examples ofdrugs useful for treating MS include Examples of drugs useful fortreating MS include corticosteroids such as methylprednisolone; IFN-βsuch as IFN-β1a and IFN-β1b; glatiramer acetate; monoclonal antibodiesthat bind to the very late antigen-4 (VLA-4) integrin such asnatalizumab; immunomodulatory agents such as FTY 720 sphinogosie-1phosphate modulator and COX-2 inhibitors such as BW755c, piroxicam, andphenidone; and neuroprotective treatments including inhibitors ofglutamate excitotoxicity and iNOS, free-radical scavengers, and cationicchannel blockers; memantine; AMPA antagonists such as topiramate; andglycine-site NMDA antagonists.

In certain embodiments, a compound of Formula (I) or a pharmaceuticalcomposition thereof may be administered to a patient for treatinginflammatory bowel disease in combination with a therapy or anothertherapeutic agent known or believed to be effective in treatinginflammatory bowel disease. Drugs useful for treating inflammatory boweldisease include cromolyn and mercaptopurine; and more particularly fortreating Crohn's disease include certolizumab, budesonide, azathioprine,sulfasalazine, metronidazole, adalimumab, mercaptopurine, infliximab,mesalamine, and natalizumab; and for treating ulcerative colitis includebalsalazide, infliximab, azathioprine, mesalamine, and cyclosporine.

In certain embodiments, a compound of Formula (I) or a pharmaceuticalcomposition thereof may be administered to a patient for treating cysticfibrosis in combination with a therapy or another therapeutic agentknown or believed to be effective in treating cystic fibrosis. Drugsuseful for treating cystic fibrosis include ivacaftor and lumacaftor.

In certain embodiments, cysteine-related compounds provided by thepresent disclosure and pharmaceutical compositions thereof may beadministered to a patient for treating asthma in combination with atherapy or another therapeutic agent known or believed to be effectivein treating asthma, or in certain embodiments, a disease, disorder, orcondition associated with asthma. Examples of drugs useful in treatingasthma include albuterol, aminophylline, beclomethasone, bitolterol,budesonide, cromolyn, ephedrine, epinephrine, flunisolide, fluticasone,formoterol, hydrocortisone, isoproterenol, levalbuterol,methylprednisolone, prednisolone, prednisone, pirbuterol,metaproterenol, racepinephrine, omalizumab, oxytriphylline, mometusone,montelukast, nedocromil, oxtriphylline, pirbuterol, salmeterol,terbutaline, theophylline, triamcinolone, zafirlukast, and zileuton.

In certain embodiments, cysteine-related compounds provided by thepresent disclosure and pharmaceutical compositions thereof may beadministered to a patient for treating chronic obstructive pulmonarydisease in combination with a therapy or another therapeutic agent knownor believed to be effective in treating chronic obstructive pulmonarydisease, or in certain embodiments, a disease, disorder, or conditionassociated with chronic obstructive pulmonary disease. Examples of drugsuseful for treating chronic obstructive pulmonary disease includealbuterol, arformoterol, azithromycin, bitolterol, epinephrine,fluticasone, formoterol, ipratropium, isoproterenol, levabuterol,metaproterenol, pirbuterol, racepinephrine, salmeterol, and tiotropium.Useful drugs for treating chronic obstructive pulmonary disease furtherinclude bronchodialators such as β2 agonists such as salbutamol,bambuterol, clenbuterol, fenoterol, and formoterol; M3 antimuscarinicssuch as ipratropium; leukotriene antagonists such as montelukast,pranlukast, and zafirlukast; cromones such as cromoglicate andnedocromil; xanthines such as theophylline; corticosteroids such asbeclomethasone, mometasone, and fluticasone; and TNF antagonists such asinfliximab, adalimumab, and etanercept. Other treatments for chronicobstructive pulmonary disease include oxygen therapy, and pulmonaryrehabilitation.

In certain embodiments, prodrugs provided by the present disclosure andpharmaceutical compositions thereof may be administered to a patient fortreating angiogenesis in combination with a therapy or anothertherapeutic agent known or believed to be effective in treatingangiogenesis. Useful drugs for treating angiogenesis includeangiostatin, endostatin, vitaxin, bevacizumab, thalidomide, batimastat,marimastat, carboxyamidotraizole, TNP-470, CM101, IFN-α, IL-12, plateletfactor-4, suramin, SU5416, thrombospondin, VEGFR, angiostatic steroids,cartilage-derived angiogenesis inhibitory factor, matrixmetalloproteinase inhibitors, 2-methoxyestradiol, tecogalan,thrombospondin, prolactin, ανβ3 inhibitors, and linomide.

In certain embodiments, prodrugs provided by the present disclosure andpharmaceutical compositions thereof may be administered to a patient fortreating transplant rejection in combination with a therapy or anothertherapeutic agent known or believed to be effective in treatingtransplant rejection. Useful drugs for treating transplant rejectioninclude calcineurin inhibitors such as cyclosporine and tacrolimus, mTORinhibitors such as sirolimus and everolimus, anti-proliferatives such asazathioprine and mycophenolic acid; corticosteroids such as monoclonalanti-IL2Rα receptor antibodies including basiliximab and daclizumab; andpolyclonal anti-T-cell antibodies including anti-thymocyte globulin andanti-lymphocyte globulin.

In certain embodiments, prodrugs provided by the present disclosure andpharmaceutical compositions thereof may be administered to a patient fortreating transplantation rejection in combination with a therapy oranother therapeutic agent known or believed to be effective in treatingtransplantation rejection. Examples of drugs useful in transplantationrejection include corticosteroids such as dexamethasone, prednisolone,and prednisone; globulins such as antilymphocyte globulin andantithymocyte globulin; macrolide immunosuppressants such as sirolimus,tacrolimus, and everolimus; mitotic inhibitors such as azathiprine,cylophosphamide, and methotrexate; monoclonal antibodies such asbasiliximab, daclizumab, infliximab, muromonoab; fungal metabolites suchas cyclosporine; and others such as glatiramer and mycophenolate.

In certain embodiments, prodrugs provided by the present disclosure andpharmaceutical compositions thereof may be administered to a patient fortreating cardiac insufficiency in combination with a therapy or anothertherapeutic agent known or believed to be effective in treating cardiacinsufficiency. Useful drugs for treating cardiac insufficiency includeantitensin-modulating agents, diuretics such as furosemide, bumetanie,hydrochlorothiazide, chlorthalidone, chlorthiazide, spironolactone,eplerenone: beta blockers such as bisoprolol, carvedilol, andmetroprolol; positive inotropes such as digoxin, milrinone, anddobutamine; alternative vasodilators such as isosorbidedinitrate/hydralazine; aldosterone receptor antagonists; recombinantneuroendocrine hormones such as nesiritide; and vasopressin receptorantagonists such as tolvaptan and conivaptan.

In certain embodiments, prodrugs provided by the present disclosure andpharmaceutical compositions thereof may be administered to a patient fortreating a mitochondrial disease such as a neurodegenerative disorder incombination with a therapy or another therapeutic agent known orbelieved to be effective in treating a mitochondrial disease such as aneurodegenerative disorder. In certain embodiments, a neurodegenerativedisorder is chosen from Alzheimer's disease, Parkinson's disease,Huntington's disease, and amyotrophic lateral sclerosis.

Therapeutic agents useful for treating Parkinson's disease includedopamine precursors such levodopa, dopamine agonists such asbromocriptine, pergolide, pramipexole, and ropinirole, MAO-B inhibitorssuch as selegiline, anticholinergic drugs such as benztropine,trihexyphenidyl, tricyclic antidepressants such as amitriptyline,amoxapine, clomipramine, desipramine, doxepin, imipramine, maprotiline,nortriptyline, protriptyline, amantadine, and trimipramine, someantihistamines such as diphenhydramine; antiviral drugs such asamantadine; and beta blockers such as propranolol.

Useful drugs for treating Alzheimer's disease include rosiglitazone,roloxifene, vitamin E, donepezil, tacrine, rivastigmine, galantamine,and memantine.

Useful drugs for treating symptoms of Huntington's disease includeantipsychotics such as haloperidol, chiorpromazine and olanzapine tocontrol hallucinations, delusions and violent outbursts; antidepressantssuch as fluoxetine, sertraline, and nortryiptyline to control depressionand obsessive-compulsive behavior; tranquilizers such asbenzodiazepines, paroxetine, venflaxin and beta-blockers to controlanxiety and chorea; mood stabilizers such as lithium, valproate, andcarbamzepine to control mania and bipolar disorder; and botulinum toxinto control dystonia and jaw clenching. Useful drugs for treatingsymptoms of Huntington's disease further include selective serotoninreuptake inhibitors (SSRI) such as fluoxetine, paroxetine, sertraline,escitalopram, citalopram, fluvosamine; norepinephrine and serotoiunreuptake inhibitors (NSRI) such as venlafaxine and duloxetine,benzodiazepines such as clonazepam, alprazolam, diazepam, and lorazepam,tricyclic antidepressants such as amitriptyline, nortnriptyline, andimipramine; and atypical antidepressants such as busipirone, bupriopion,and mirtazepine for treating the symptoms of anxiety and depression;atomoxetine, dextroamphetamine, and modafinil for treating apathysymptoms; amantadine, memantine, and tetrabenazine for treating choreasymptoms; citalopram, atomoxetine, memantine, rivastigmine, anddonepezil for treating cognitive symptoms; lorazepam and trazedone fortreating insomma; valproate, carbamazepine and lamotrigine for treatingsymptoms of irritability; SSRI antidepressants such as fluoxetine,paroxetine, sertaline, and fluvoxamine, NSRI antidepressants such asvenlafaxine, and others such as mirtazepine, clomipramine, lomotrigine,gabapentin, valproate, carbamazepine, olanzapine, rispiridone, andquetiapine for treating symptoms of obsessive-compulsive disorder;haloperidol, quetiapine, clozapine, risperidone, olanzapine,ziprasidone, and aripiprazole for treating psychosis; and pramipexole,levodopa and amantadine for treating rigidity.

Useful drugs for treating ALS include riluzole. Other drugs of potentialuse in treating ALS include memantine, tamoxifen, thalidomide,ceftriaxone, sodium phenyl butyrate, celecoxib, glatiramer acetate,busipirone, creatine, minocycline, coenzyme Q10, oxandrolone, IGF-1,topiramate, xaliproden, and indinavir. Drugs such as baclofen anddiazepam can be useful in treating spasticity associated with ALS.

In certain embodiments, a compound of Formula (I) or a pharmaceuticalcomposition thereof may be administered to a patient in combination witha therapy or another therapeutic agent known or believed to be effectivein inhibiting TNF function.

Examples of drugs known to inhibit TNF function include infliximab,adalimumab, etanercept, certolizumab, goliimumab, pentoxifylline,quanylhydrozone, thalidomide, flavonoids such as narigenin, resveratoland quecetin, alkaloids such as lycorine, terpenes such as acanthoicacid, fatty acids such as 13-HOA, and retinoids such as retinoic acid.

EXAMPLES

The following examples describe in detail the synthesis of compounds ofFormula (I), properties of compounds of Formula (I), and uses ofcompounds of Formula (I). It will be apparent to those skilled in theart that many modifications, both to materials and methods, may bepracticed without departing from the scope of the disclosure.

General Experimental Protocols

All reagents and solvents that can be purchased from commercialsuppliers may be used without further purification or manipulation.Non-commercially available reagents may be synthesized from commerciallyavailable starting materials, and by adapting methods well known in theart.

Analytical LC/MS was performed on a Agilent 1100 equipped with AB SciexAPI 2000 or a Waters 2790 equipped with a Waters Micromass QZ massspectrometer and a Phenomenex Luna C-18 analytical column. PreparativeHPLC purification was performed on a Agilent 1100. Both analytical andpreparative HPLC used acetonitrile/water gradients containing 0.05%formic acid. Normal-phase silica gel purification was performed on aISCO CombiFlash Companion purification system using either a mixture ofmethanol and dichloromethane or ethyl acetate and hexanes. Chemicalnames were generated with Accelrys Draw 4.1 SP1, version MDL.Draw.Editor4.1. 100.70 (Accelrys, Inc., San Diego, Calif.).

General Synthetic Procedure

General Procedure: Thiocarbonate/Carbamate Formation

An amino- and/or thiol-containing compound (1.0 equivalent) is combinedwith activated ester such as(2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl acetate (1.0 to 3.0equivalents) in 1-20 mL/1.0 mmol of an inert solvent such asdichloromethane (DCM), ethyl acetate (EtOAc), N-methylpyrrolidone (NMP),N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA, DMAc),acetonitrile (ACN, MeCN), dimethylsulfoxide (DMSO), tetrahydrofuran(THF), toluene, water, or mixtures thereof. To the solution, anappropriate inorganic base (1.0 to 5.0 equivalents) such as NaHCO₃,Na₂CO₃, KHCO₃, K₂CO₃, CsHCO₃, and Cs₂CO₃ or an organic secondary ortertiary base such as dicyclohexylamine (DCHA), triethylamine (TEA), anddiisopropylethylamine (DIEA) is added. The reaction mixture is stirredfrom about 1 to about 72 h at a temperature between 0° C. to 40° C. Themixture is then diluted with an appropriate organic solvent such asmethyl tert-butyl ether (MTBE), diethyl ether (Et₂O), ethylacetate(EtOAc), dichloromethane (DCM), or mixtures thereof, washed with waterand brine, and dried over anhydrous sodium sulfate (Na₂SO₄) or magnesiumsulfate (MgSO₄). After filtration, the organic solvents are removedunder reduced pressure using a rotary evaporator. If required, the crudereaction products are further purified by well known purificationtechniques such as silica gel flash column chromatography, mass-guidedreversed-phase preparative HPLC/lyophilization, precipitation, orcrystallization.

Example 1 (2R)-2-Acetamido-3-(acetoxymethoxycarbonylsulfanyl)propanoicacid (1)

A mixture of N-acetyl-L-cysteine (0.10 g, 1.0 eq),(2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl acetate (1.0 eq), andNaHCO₃ (or TEA) (3.0 eq) in ACN/water (or DMF) (5 mL) was stirred at 20°C. overnight. The reaction was concentrated in vacuo to a residue andthen purified by reverse-phase (C-18) liquid chromatography using waterand acetonitrile as eluents to yield compound (1). MS (ESI): m/z 280.0(M+H)+.

Example 2(2R)-2-Acetamido-3-(2-methylpropanoyloxymethoxycarbonylsulfanyl)propanoicacid (2)

Compound (2) was prepared according to the method described in Example 1and substituting (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl acetatewith (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 2-methylpropanoate.MS (ESI): m/z 308.1 (M+H)+.

Example 3(2R)-2-Acetamido-3-(2,2-dimethylpropanoyloxymethoxycarbonylsulfanyl)propanoicacid

Compound (3) was prepared according to the method described in Example 1and substituting (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl acetatewith (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl2,2-dimethylpropanoate. MS (ESI): m/z 322.1 (M+H)+.

Example 4(2R)-2-Acetamido-3-(cyclohexanecarbonyloxymethoxycarbonylsulfanyl)propanoicacid (4)

Compound (4) was prepared according to the method described in Example 1and substituting (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl acetatewith (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethylcyclohexanecarboxylate. MS (ESI): m/z 348.1 (M+H)+.

Example 5(2R)-2-Acetamido-3-(benzoyloxymethoxycarbonylsulfanyl)propanoic acid (5)

Compound (5) was prepared according to the method described in Example 1and substituting (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl acetatewith (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl benzoate. MS (ESI):m/z 342.1 (M+H)+.

Example 6(2R)-2-(Acetoxymethoxycarbonylamino)-3-(acetoxymethoxycarbonylsulfanyl)propanoicacid (6)

A mixture of L-cysteine (0.10 g, 1.0 eq),(2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl acetate (3.0 eq), andtrimethylamine (5.0 eq) in DMF (or ACN/water) (10 mL) was stirred at 20°C. overnight. The reaction was concentrated in vacuo to a residue andthen purified by reverse-phase (C-18) liquid chromatography using waterand acetonitrile as eluents to yield compound (6). MS (ESI): m/z 354.0(M+H)+.

Example 7(2R)-2-(2-Methylpropanoyloxymethoxycarbonylamino)-3-(2-methylpropanoyloxymethoxycarbonylsulfanyl)propanoicacid (7)

Compound (7) was prepared according to the method described in Example 6and substituting (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl acetatewith (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 2-methylpropanoate.MS (ESI): m/z 410.1 (M+H)+.

Example 8(2R)-2-(2,2-Dimethylpropanoyloxymethoxycarbonylamino)-3-(2,2-dimethylpropanoyloxymethoxycarbonylsulfanyl)propanoicacid (8)

Compound (8) was prepared according to the method described in Example 6and substituting (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl acetatewith (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl2,2-dimethylpropanoate. MS (ESI): m/z 438.1 (M+H)+.

Example 9(2R)-2-(Cyclohexanecarbonyloxymethoxycarbonylamino)-3-(cyclohexanecarbonyloxymethoxycarbonylsulfanyl)propanoicacid (9)

Compound (9) was prepared according to the method described in Example 6and substituting (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl acetatewith (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethylcyclohexanecarboxylate. MS (ESI): m/z 490.2 (M+H)+.

Example 10(2R)-2-(Benzoyloxymethoxycarbonylamino)-3-(benzoyloxymethoxycarbonylsulfanyl)propanoicacid (10)

Compound (10) was prepared according to the method described in Example6 and substituting (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethylacetate with (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl benzoate. MS(ESI): m/z 478.1 (M+H)+.

Example 11(2S)-2-(Acetoxymethoxycarbonylamino)-3-(acetoxymethoxycarbonylsulfanyl)-3-methyl-butanoicacid (11)

A mixture of D-penicillamine (0.10 g, 1.0 eq),(2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl acetate (3.0 eq), andtrimethylamine (5.0 eq) in DMF (or ACN/water) (10 mL) was stirred at 20°C. overnight. The reaction was concentrated in vacuo to a residue andthen purified by reverse-phase (C-18) liquid chromatography using waterand acetonitrile as eluents to yield compound (11). MS (ESI): m/z 382.1(M+H)+.

Example 12(2S)-3-Methyl-2-(2-methylpropanoyloxymethoxycarbonylamino)-3-(2-methylpropanoyloxymethoxycarbonylsulfanyl)butanoicacid (12)

Compound (12) was prepared according to the method described in Example11 and substituting (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethylacetate with (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl2-methylpropanoate. MS (ESI): m/z 438.1 (M+H)+.

Example 13(2S)-2-(2,2-Dimethylpropanoyloxymethoxycarbonylamino)-3-(2,2-dimethylpropanoyloxymethoxycarbonylsulfanyl)-3-methyl-butanoicacid (13)

Compound (13) was prepared according to the method described in Example11 and substituting (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethylacetate with (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl2,2-dimethylpropanoate. MS (ESI): m/z 466.2 (M+H)+.

Example 14(2S)-2-(Cyclohexanecarbonyloxymethoxycarbonylamino)-3-(cyclohexanecarbonyloxymethoxycarbonylsulfanyl)-3-methyl-butanoicacid (14)

Compound (14) was prepared according to the method described in Example11 and substituting (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethylacetate with (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethylcyclohexanecarboxylate. MS (ESI): m/z 518.2 (M+H)+.

Example 15(2S)-2-(Benzoyloxymethoxycarbonylamino)-3-(benzoyloxymethoxycarbonylsulfanyl)-3-methyl-butanoicacid (15)

Compound (15) was prepared according to the method described in Example11 and substituting (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethylacetate with ((2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl benzoate.MS (ESI): m/z 506.1 (M+H)+.

Example 16(2R)-2-Acetamido-3-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonylsulfanyl]propanoicacid (16)

A mixture of N-acetyl-L-cysteine (0.20 g, 1.0 eq),(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl carbonochloridate (or(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (4-nitrophenyl) carbonate) (1.0to 2.5 eq), and NaHCO₃ (or TEA) (3.0 eq) in ACN/water (or DMF) (15 mL)was stirred at 20° C. overnight. The reaction was concentrated in vacuoto a residue and then purified by reverse-phase (C-18) liquidchromatography using water and acetonitrile as eluents to yield compound(16). MS (ESI): m/z 320.0 (M+H)+.

Example 17 Ethyl(2R)-2-acetamido-3-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonylsulfanyl]propanoate(17)

Compound (17) was prepared according to the method described in Example16 and substituting N-acetyl-L-cysteine with N-acetyl-L-cysteine ethylester. MS (ESI): m/z 348.1 (M+H)+.

Example 18(2R)-2-[(5-Methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonylamino]-3-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonylsulfanyl]propanoicacid (18)

Compound (18) was prepared according to the method described in Example16 and substituting N-acetyl-L-cysteine with L-cysteine. MS (ESI): m/z434.0 (M+H)+.

Example 19(2S)-3-Methyl-2-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonylamino]-3-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonylsulfanyl]butanoicacid (19)

A mixture of D-penicillamine (0.20 g, 1.0 eq),(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl carbonochloridate (or(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (4-nitrophenyl) carbonate) (2.0eq), and NaHCO₃ (or TEA) (3.0 eq) in ACN/water (or DMF) (15 mL) wasstirred at 20° C. overnight. The reaction was concentrated in vacuo to aresidue and then purified by reverse-phase (C-18) liquid chromatographyusing water and acetonitrile as eluents to yield compound (19). MS(ESI): m/z 462.1 (M+H)+.

The invention claimed is:
 1. A compound according to Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: each R¹ ischosen from hydrogen and methyl; R² is chosen from hydrogen, C₁₋₆ alkyl,C₃₋₁₂ cycloalkyl, and C₅₋₁₀ aryl; W¹ is chosen from substituents ofFormula (I-a) and Formula (I-b); and W² is chosen from hydrogen andsubstituents of Formula (I-a), Formula (I-b), and Formula (I-c):

wherein R³, R⁴, R⁵, R⁶, and R⁷ are independently chosen from hydrogen,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,n-pentyl, n-hexyl, cyclohexyl, phenyl, and benzyl; and Y¹ is chosen froma bond and —O—.
 2. The compound according to claim 1, wherein each R¹ ishydrogen.
 3. The compound according to claim 1, wherein each R¹ ismethyl.
 4. The compound according to claim 1, wherein R² is chosen fromhydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclohexyl,phenyl, and benzyl.
 5. The compound according to claim 1, wherein R² ishydrogen.
 6. The compound according to claim 1, wherein W¹ is chosenfrom the substituents of Formula (I-a) and Formula (I-b), wherein R³,R⁴, R⁵, and R⁶ are independently chosen from hydrogen, methyl, ethyl,isopropyl, tert-butyl, cyclohexyl, phenyl, and benzyl; and Y¹ is chosenfrom a bond and —O—.
 7. The compound according to claim 1, wherein W¹ ischosen from the substituent of Formula (I-a), wherein R³ is chosen frommethyl, ethyl, isopropyl, tert-butyl, cyclohexyl, phenyl, and benzyl; R⁴and R⁵ are hydrogen; and Y¹ is a bond.
 8. The compound according toclaim 1, wherein W² is chosen from hydrogen and the substituents ofFormula (I-a), Formula (I-b), and Formula (I-c), wherein R³, R⁴, R⁵, R⁶,and R⁷ are independently chosen from hydrogen, methyl, ethyl, isopropyl,tert-butyl, cyclohexyl, phenyl, and benzyl; and Y¹ is chosen from a bondand —O—.
 9. The compound according to claim 1, wherein W² is chosen fromhydrogen and the substituents of Formula (I-a), Formula (I-b), andFormula (I-c), wherein R³ is chosen from methyl, ethyl, isopropyl,tert-butyl, cyclohexyl, phenyl, and benzyl; R⁴ and R⁵ are hydrogen; R⁶and R⁷ are methyl; and Y¹ is a bond.
 10. The compound according to claim1, wherein each R¹ is chosen from hydrogen and methyl; R² is chosen fromhydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclohexyl,phenyl, and benzyl; W¹ is chosen from the substituents of Formula (I-a)and Formula (I-b); and W² is chosen from hydrogen and the substituentsof Formula (I-a), Formula (I-b), and Formula (I-c).
 11. The compoundaccording to claim 1, wherein each R¹ is hydrogen; R² is hydrogen; W¹ isthe substituent of Formula (I-a), wherein R³ is methyl, R⁴ and R⁵ arehydrogen, and Y¹ is a bond; and W² is the substituent of Formula (I-c),wherein R⁷ is methyl.
 12. The compound according to claim 1, whereineach R¹ is hydrogen; R² is hydrogen; and W¹ and W² are the substituentof Formula (I-a), wherein R³ is methyl, R⁴ and R⁵ are hydrogen, and Y¹is a bond.
 13. The compound according to claim 1, wherein each R¹ ismethyl; R² is hydrogen; and W¹ and W² are the substituent of Formula(I-b), wherein R⁶ is methyl.
 14. The compound according to claim 1,wherein the compound is chosen from the compounds of Formula (I-A-1),Formula (I-A-3), Formula (I-A-4), Formula (I-A-5), Formula (I-A-6),Formula (I-B-1), Formula (I-B-2), Formula (I-B-3), Formula (I-B-4),Formula (I-B-5), Formula (I-H-1), Formula (I-H-2), Formula (I-I-1),Formula (I-AA-1), Formula (I-AA-2), Formula (I-AA-3), Formula (I-AA-4),Formula (I-AA-5), and Formula (I-DD-1):


15. A pharmaceutical composition comprising a pharmaceuticallyacceptable vehicle and a therapeutically effective amount of a compoundselected from the compounds listed in claim
 14. 16. The pharmaceuticalcomposition according to claim 15, wherein the composition is suitablefor oral, inhalation, or topical administration.
 17. The pharmaceuticalcomposition according to claim 15, wherein the compound is present in anamount that is effective for the treatment of a disease chosen from aliver disease.
 18. The pharmaceutical composition according to claim 15,wherein the compound is present in an amount that is effective for thetreatment of a disease chosen from paracetamol overdose and Wilson'sdisease.
 19. The pharmaceutical composition according to claim 15,wherein the composition is suitable for sustained release formulation.20. The pharmaceutical composition according to claim 15, wherein thecomposition is suitable for controlled release formulation.